PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of pparresJournal's HomeManuscript SubmissionAims and ScopeAuthor GuidelinesEditorial BoardHome
 
PPAR Res. 2010; 2010: 814609.
Published online 2010 February 28. doi:  10.1155/2010/814609
PMCID: PMC2829627

Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

Abstract

The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-γ agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARγ agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARγ agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARγ and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.

1. Introduction

Peroxisome proliferator activated receptors (PPARs) are a subfamily of the larger nuclear hormone receptor superfamily of transcription factors [1, 2]. Three distinct but closely related isoforms designated PPARα, PPARβ/δ, and PPARγ make up the family. PPARγ functions are further delineated by two isoforms PPARγ1 and PPARγ2, which arise due to alternative promoter usage accompanied by alternative splicing and/or polyadenylation of the primary transcript (recently reviewed in [3]). PPARs are best known for their roles in lipid homeostasis and energy metabolism including cholesterol and triglyceride turnover [4], obesity [5], metabolic syndrome [69], and diabetes [5, 10, 11]; however, since their discovery, the PPARs and/or PPAR agonists have been implicated in a broader spectrum of biological processes playing protective and homeostatic roles such as promoting wound healing [12, 13] and, for the most part, countering the effects of aging [14], cardiovascular disease [15, 16], inflammation and immune responses [1719], thrombosis and hemostasis [7, 8, 1721], pathological angiogenesis [2232], and cancer [24, 25, 3141].

A number of naturally occurring ligands activate PPARγ (Table 1), such as unsaturated fatty acids and eicosanoids [42], 15-deoxy-Δ-12-14-prostaglandin J2 (15d-PGJ2), and components of oxidized low density lipoproteins (LDLs) [43]. The affinity of PPARγ for many of the endogenous ligands is low and, in some cases the physiological relevance of the ligand needs to be determined. However, it is well accepted that 15d-PGJ2 is the most potent endogenous ligand for PPARγ. The thiazolidinediones (TZDs) are a class of synthetic ligands with high affinity for PPARγ that are used for their antidiabetic effects to sensitize cells to insulin [44]. Nonsteroidal anti-inflammatory drugs such as ibuprofen and indomethacin are low affinity PPARγ ligands [45]. Furthermore, the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), and derivatives are high affinity ligands for PPARγ [46] (Table 1).

Table 1
PPAR-γ ligands.

Two overarching principles should be kept in mind when weighing the plethora of therapeutic benefits touted for PPARγ agonists. First, PPARγ agonists evoke both PPARγ-dependent and PPARγ-independent effects, thus therapeutic benefits ascribed to certain PPARγ ligands do not necessarily require interaction with the PPARγ ligand binding domain. Although PPARγ-independent effects induced by 15d-PGJ2 and CDDO are due in part to the electrophilic nature of these ligands [4750], PPARγ-independent effects induced by TZDs are through a number of signaling pathways including inhibition of Bcl-2/Bcl-xL function, proteasomal degradation of cell cycle- and apoptosis-regulatory proteins, and transcriptional repression [51]. Second, PPARγ agonists have been shown to have paradoxical physiological effects, likely due to tissue-specific and/or context-dependent regulatory signaling events.

Recently, we reviewed the role of PPARγ and its ligands in the treatment of hematological malignancies, which is summarized in Tables Tables1 and1 and and2 2 [3]. The purpose of this paper is twofold: first to highlight the potential uses for PPARγ agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies, and second, to review the potential role PPARγ and PPARγ ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow—two pathophysiological events associated with most all types of cancer including hematological malignancies.

Table 2
PPARγ and PPARγ ligands as potential therapy for hematological malignancies.

2. Tumor-Stromal Microenvironment Crosstalk and Tumor-Associated Angiogenesis

2.1. Cancer Stem Cell Theory and Tumor Dormancy

A key issue of debate in cancer biology is whether tumor growth is caused by a substantial proportion of the tumor cells or exclusively by an infrequent subpopulation of cells termed cancer stem cells (CSCs) [52]. Regardless of the cancer type, most patients who have experienced many years of disease-free survival after successful treatment of the primary tumor ultimately die from metastatic disease. Patients who relapse must harbor cancer cells for years or even decades until the cancer cells overcome the regulatory mechanisms that keep the tumor in check. Dormant cancer cells are defined by a prolonged absence of or a balance in either proliferation or apoptosis, resulting in essentially a perpetual state of quiescence that protects them from conventional cytotoxic drugs, which only target actively proliferating cells. It is unknown whether dormant cancer cells represent a specialized subpopulation of cells programmed to stay dormant, an unspecialized population of cells not able to grow in the new microenvironment, or a combination of both [53]. CSCs are usually slowly cycling cells and thus insensitive to cytotoxic drugs as well [54, 55]. Dormant cancer cells are inferred to be CSCs or tumor initiating cells, as some prefer to call them [56]. Nonetheless, the relative frequency of CSCs varies as a function of both the tumor type and the specific experimental system used [57]. To date, published data most strongly support the presence of CSCs in hematologic malignancies such as leukemia [58], and in three major solid tumor types, including aggressive brain, breast, and colon cancers [59, 60]. Moreover, the existence of treatment resistant tumor cells following disease relapse has bolstered the theory that CSCs exist [56]. Thus, new approaches to target CSCs are actively being sought.

Although little evidence is available to suggest whether PPARγ agonists could be used to specifically target CSCs while sparing normal hematopoietic stem cells, a few studies have been reported. Chearwae and Bright [61] demonstrated that PPARγ agonists inhibit the proliferation of brain CSCs by inducing cell cycle arrest and apoptosis, which was associated with upregulated expression of PPARγ and inhibition of signal transducer and activator of transcription (Stat)-3 signaling. Saiki and colleagues [62] showed that pioglitazone inhibits the growth of human leukemia cell lines and primary leukemia cells while sparing normal stem cells. Preclinical testing has identified additional cancer therapeutics that selectively target leukemic stem cells but not normal stem cells, including idarubicin with the proteasome inhibitor, parthenolide (known as feverfew), and TDZD-8 [63]. These agents target the NF-κB pathway, a critical link in the well-established association between inflammation and carcinogenesis. In that PPARγ agonists inhibit both NF-κB- and Stat3-mediated transactivation of target genes and both of these transcription factors play a prominent role in cancer progression (see Section 2.8 and references therein), it is a likely extension to consider a role for PPARγ agonists to target CSCs.

2.2. Tumor-Associated Angiogenesis

Regardless of the type of cancer, once a primary tumor becomes established, it needs to develop its own blood supply for nutrient delivery and removal of toxic waste. The process of angiogenesis, that is the formation of new blood vessels from existing vasculature, involves complex interplay among cancer and stromal cell-secreted factors, extracellular matrix (ECM) constituents, and endothelial cells (ECs) (Figure 1). The adult vasculature is composed of quiescent ECs lining blood vessels and, with the exception of reproduction; the process of angiogenesis begins only in response to a broad array of tissue injury.

Figure 1
Molecular mechanisms of tumor-associated angiogenesis. Angiogenesis is essential for the persistence of solid tumor growth and, only recently, has it been appreciated that angiogenesis plays a role in progression of hematological malignancies as ...

Several isoforms of VEGF-A/165 are produced by alternative mRNA processing of the primary transcript, and these isoforms differ primarily in their ability to adhere to heparin or heparan sulfate proteoglycans (HSPGs) found both in the ECM or on the surface of stromal and tumor cells [72]. The VEGF gene family encodes VEGF isoforms A-F and placenta growth factor (PLGF) with at least three cognate receptors, VEGFR1/Flt-1, VEGFR2/Flk-1/KDR, VEGFR3/Flt-4 and two coreceptors, neuropilin (NRP) and HSPGs. VEGF-A/165 (hereafter designated VEGF) signaling through VEGFR2 is the major isoform responsible for pathological angiogenesis and induction of vascular permeability in tumors [73, 74], which leads to enhanced transendothelial migration of cancer cells during intravasation and extravasation [75]. VEGF-C and VEGF-D bind to VEGFR2 as well as VEGFR3 and are important for lymphangiogenesis and cancer metastasis to lymph nodes and spread through the lymphatic system [7678].

VEGF production and intracrine signaling through VEGFR2 by ECs is essential for vascular homeostasis but is dispensable for angiogenesis as shown in EC-specific VEGF knockout mice [79]. Intracrine VEGF signaling requires expression of both VEGF and VEGFRs by the same cell and resistance to VEGF inhibitors that fail to penetrate the intracellular compartment. Hematopoietic stem cell survival also involves a VEGF-dependent internal autocrine loop mechanism [80]. Although it was originally thought that VEGFR expression was restricted to ECs, it is now apparent that other cell types express functional VEGFRs. Furthermore, VEGF is an autocrine growth factor for VEGFR-positive human tumors, including Kaposi sarcoma, melanoma, breast, ovarian, pancreatic, thyroid and prostate carcinomas, and leukemia [8187]. Thus, in VEGFR-expressing tumors, VEGF inhibition may directly inhibit tumor cell growth as well as tumor-associated angiogenesis [83]. A host of proangiogenic factors play a role in pathological angiogenesis [64]; however, since most anticancer therapeutic strategies target the VEGF signaling pathway [64, 88], this paper focuses thereon.

2.3. Tumor-Stromal Microenvironment

Paget's “seed and soil” hypothesis emphasizes the importance of the interaction between the tumor cell (“seed”) and its environment (“soil”) for metastasis to occur (reviewed in [89]). The stroma of the tumor microenvironment consists of several components including growth factors, chemokines, matrix glycoproteins and proteoglycans, proteases, and host cells that influence the behavior of cancer cells (reviewed in [90102]). Host ECs, pericytes, macrophages, dendritic cells, lymphocytes, adipocytes, and fibroblasts/myofibroblasts present in the tumor microenvironment participate in the metastatic process (Figure 2). Initiation of new blood vessel formation requires activation of matrix metalloproteinases (MMPs) leading to degradation of the basement membrane, sprouting of ECs, and regulation of pericyte attachment for vessel stabilization. Activated fibroblasts, myofibroblasts, play an important role in synchronizing these events [94]. Furthermore, the topography of the ECM mediates vascular development and regulates the speed of cell migration during angiogenesis [103].

Figure 2
Tumor-associated angiogenesis is sustained through stromal microenvironment crosstalk. Most tumors are associated with the activation of tumor-promoting innate immune responses involving neutrophils, macrophages, and NK cells. Specific (adaptive) ...

Chronic inflammation is associated with cancer initiation and progression [104106]. Vascular ECs play a pivotal role in regulating leukocyte recruitment during inflammation [90]. Thus, in most cases, cancers exploit inflammation and recruited inflammatory cells for their own benefit [91]. Although activated inflammatory cells in the tumor microenvironment play important roles in cancer initiation, progression, angiogenesis, and metastasis [92], they are not the most numerous. Cancer-associated fibroblasts, which resemble myofibroblasts of healing wounds, are the most abundant cells of the tumor stroma [93], and contribute significantly to chronic inflammation, production of proangiogenic factors, and metastasis [94].

2.4. Inhibitors of Angiogenesis

As discussed above, angiogenesis is the hallmark pathology in tumor growth, progression, and metastasis. Inhibiting tumor angiogenesis adds to the arsenal of treatment options for a number of solid tumor types [111, 112], and recently has been proposed for hematological malignancies as well [107, 113119]. Endogenous inhibitors of angiogenesis are critical for tight regulation of pathological angiogenesis; however, in response to malignant transformation the putative “angiogenic switch” bypasses this tight regulation to promote tumor progression [120]. Whereas radiation and chemotherapy target killing of the tumor cells, antiangiogenic therapy is primarily directed against tumor blood vessels. Endostatin [121, 122], angiostatin [122], and TSP-1 [123] are among a host of well-known endogenous inhibitors of angiogenesis [98, 124]. TSP-1 is a large molecular weight glycoprotein that inhibits the proliferation and migration of ECs by interacting with CD36 expressed on the cell surface; CD36 is a PPARγ target gene. Small molecules based on a CD36-binding peptide sequence from TSP-1 are being tested for cancer treatment. One analog, ABT510, exhibits potent proapoptotic activity in vitro, while clinically it is very well tolerated with therapeutic benefits against several malignancies reported in phase II clinical trials [125129].

Targeting VEGF-induced angiogenesis is in current use as monotherapy or combination therapy to treat a wide variety of cancers [130132]. Bevacizumab (Avastin) and ranibizumab (Lucentis) are FDA-approved humanized monoclonal antibodies that recognize and block VEGF signaling in cancer and age-related macular degeneration (AMD) [130134]. Additional, but not all-inclusive VEGF inhibitors (direct or indirect) are the RNA aptamer, pegaptanib; VEGF receptor decoy, VEGF-Trap (Aflibercept); small interfering RNA-based therapies, bevasiranib, and AGN211745; rapamycin, sirolimus; tyrosine kinase inhibitors including vatalanib, pazopanib, imatinib (Gleevec), TG100801, TG101095, AG013958, and AL39324; soluble VEGFRs; proteasome inhibitors, bortezomib (Velcade); thalidomide and derivatives.

At present, established therapies have been very successful in reducing the vision loss associated with AMD [135, 136]; however, a number of reports on the clinical outcomes of antiangiogenic therapy with VEGF inhibitors have shown equivocal results [88, 137141]. Unfortunately, no significant survival benefit has been demonstrated in anti-VEGF monotherapy trials. When anti-VEGF inhibitors are used in combination with standard chemotherapeutic approaches for solid tumors, such treatment does not prolong survival of cancer patients for more than a few months [137141], except as shown in phase II and phase III clinical trials for metastatic colon cancer and metastatic breast cancer where median survival over chemotherapy alone was extended ~15–26 months (reviewed in [142]). Although different classes of VEGF-targeted therapies inhibit primary tumor growth, recent studies surprisingly report that treatment with VEGF inhibitors leads to more invasive and metastatic tumors [139, 143]. Most patients who initially respond to VEGF-targeted therapy will develop resistance, and the molecular and cellular mechanisms promoting resistance are poorly understood [137, 138]. Thus, resistance or refractoriness of tumor ECs to treatment with VEGF inhibitors limits the utility of long-term treatment [143]. These findings indicate that new studies and molecular approaches are needed to overcome the lack of sensitivity or resistance of tumor ECs to antiangiogenic therapies.

2.5. Targeting Transcription Factor Signaling Pathways Activated in Angiogenesis

Although VEGF is upregulated in response to many inducers activated in cancer, only two major transcription factors have been identified for its promoter, hypoxia inducible factor (HIF)-1 and Stat3 [144]. Both HIF-1 production and Stat3 activity are upregulated in many types of cancer. VEGF is strongly induced by the hypoxic tumor microenvironment before the tumor becomes vascularized, and thus, is important in hypoxic regulation of angiogenesis [145, 146]. HIF-1 is composed of the constitutively expressed HIF-1β subunit (aka the aryl hydrocarbon nuclear translocator/ARNT [146]) and an O2- and growth factor-regulated HIF-1α subunit. HIF-1α is also constitutively expressed but rapidly degraded under normoxia due to hydroxylation at two proline residues within the central degradation domain. Hydroxylation increases the affinity of HIF-1α for the tumor suppressor protein von Hippel-Lindau (pVHL) E3 ligase complex, which mediates ubiquitination and proteasomal degradation of HIF-1α thereby preventing formation of an active HIF-1 heterodimer [147]. Because the HIF hydroxylases have an absolute requirement for oxygen, hydroxylation is suppressed under hypoxic conditions allowing the HIF-1α subunit to accumulate, translocate to the nucleus, and heterodimerize with HIF-1β to activate transcription of target genes [148].

Activation of the Jak/Stat3 pathway by IL-6 through its high affinity receptor, IL-6Rα, and its binding partner, gp130, is a well-known inflammatory response evoked by the acute phase response of innate immunity [149, 150]. Stat3 is a latent transcription factor whose maximal activation requires both tyrosine (Y-705) and serine (S-727) phosphorylation. Inhibition of Stat3 activation blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo [151]. Activation of Stat3 signaling by various mitogens is prevalent in different types of cancers. Furthermore, when Stat3 is inhibited, tumor cells will no longer express proangiogenic mediators in response to IL-6R signaling. Because Stat3 is constitutively active in many types of cancers, it is considered oncogenic [152, 153]. Therefore, Stat3 is an apt upstream target for inhibiting tumor VEGF expression and angiogenesis [151].

NF-κB transcription factor links inflammation and tumorigenesis, and its activation allows both premalignant and malignant cells to escape apoptosis [154]. NF-κB signaling occurs in essentially all aspects of cancer progression from uncontrolled growth, evasion of apoptosis, tumor cell invasion through stromal compartments and into the blood stream, and sustained angiogenesis [104, 154]. Constitutive NF-κB activation is found in lymphoid and myeloid malignancies, including preneoplastic conditions, emphasizing its role in malignant transformation [155, 156]. More than 200 genes involved in cell survival, apoptosis, cell growth, immune responses and inflammation are transactivated by NF-κB [157]. NF-κB is sequestered in the cytoplasm by inhibitor proteins such as IκBα [104, 154156]. Upon activation, proteasomal degradation of IκBα releases NF-κB, which then translocates to the nucleus to bind to the κB response element in promoter regions of target genes. Thus, small inhibitory molecules that target these various steps are continually being sought for cancer treatment. PPARγ agonists have anti-inflammatory properties that are conferred, in part, through their ability to inactivate transcription factors that regulate inflammation including Stat3, NF-κB, and AP-1 [158160]. The potential for PPARγ agonists as inhibitors of Stat3 and NF-κB survival signaling in hematological malignancies is discussed in Section 2.8.

2.6. Angiogenesis and Targeted Antiangiogenic Therapy in Hematological Malignancies

Since hematological malignancies originate in bone marrow and lymphatic organs and do not form solid tumor masses, it was generally believed that angiogenesis would not be as critical for cancer progression as in solid tumors. In the recent years, however, the importance of angiogenesis and lymphangiogenesis in hematological malignancies has been recognized and discussed in detail in a number of excellent reviews and references therein [113, 114, 116119]. Because PPARγ agonists are being tested as inhibitors of angiogenesis, it is important to understand the role of angiogenesis and associated signal transduction pathways in the progression of hematological malignancies. Increased bone marrow microvessel density (MVD), an in vivo measure of tumor-associated angiogenesis, is found in hematological malignancies [161], confirming the importance of angiogenesis for malignant progression.

In general, increased MVD correlates with increased disease burden and poor prognosis or treatment outcome [118]. A number of antiangiogenic agents have been used to treat hematological malignancies as discussed in the review articles cited above. For example, thalidomide, well known as a potent teratogen causing stunted limb growth, has gained favor as an inhibitor of angiogenesis in multiple myeloma (MM) [162167]. Thalidomide and similar immunomodulatory drugs and proteasome inhibitors (e.g., bortezomib) exert their effects directly by induction of apoptosis of MM cells or indirectly by inhibiting production of cytokines and proangiogenic factors, including VEGF, by bone marrow stromal cells (BMSCs) [162, 168]. The angiogenic activity of MM ECs correlates with downregulated expression of the endogenous antiangiogenic factor, endostatin [169]. Increased MVD in bone marrow correlates with shorter overall disease-free survival in AML, and elevated VEGF mediates both autocrine and paracrine signaling in support of leukemia cell survival and induction of angiogenesis [86, 87, 113, 161].

Angiogenesis in chronic lymphocytic leukemia (CLL) occurs in both marrow and lymph nodes [170]. Increased vascularity leads to elevated production of hematopoietic growth factors by new vessel ECs, which stimulates expression of VEGF and VEGFRs by CLL cells for autocrine signaling to promote survival [113, 170]. Elevated levels of VEGF are found in the serum of patients with chronic myeloid leukemia (CML), which correlates with worse survival [171]. Non-Hodgkin lymphoma (NHL) cells secrete VEGF and express VEGFRs, which also contribute to autocrine and paracrine signaling [172]. A phase II clinical trial of bevacizumab (Avastin) therapy in patients with relapsed, aggressive NHL showed a median increase in disease-free survival by 5.2 months [115], suggesting that anti-VEGF therapy is a limited but viable target for treatment. Antiangiogenic therapy would likely be more efficacious if combined with active chemotherapy regimens [115, 173]. Increased MVD in lymph nodes and elevated VEGF are statistically correlated with a greater tumor burden in Hodgkin lymphoma in newly diagnosed patients [174, 175]. Survival after treatment of diffuse large-B-cell lymphoma is adversely affected in patients whose tumor stroma show elevated MVD, indicating that differences in the tumor microenvironment play a critical role in treatment outcomes [176]. However, the role of angiogenesis varies in lymphoma subtypes due to heterogeneity in expression of proangiogenic factors [113, 177].

In addition to agents targeting VEGF-VEGFR signaling directly, a number of agents have been developed to target the tumor microenvironment (reviewed in [99102]), including ECM modulators, tyrosine kinase inhibitors, and immunomodulators, many of which indirectly target cancer angiogenesis. Nonetheless, autocrine VEGF signaling to promote malignant cell survival appears to be a common theme in hematological malignancies [8587, 107, 113, 170, 172, 178], suggesting that anti-VEGF/VEGFR targeted therapy would promote direct killing of tumor cells, as well as inhibit angiogenesis associated with several types of hematological malignancies. It should be noted that antiangiogenic therapy in combination with conventional therapy for metastatic colon cancer and metastatic breast cancer significantly increased survival [142]; these cancers represent two of the three solid tumors (the third being brain cancer) for which published data most strongly support the presence of CSCs [59, 60]. In that CSCs have been documented in hematologic malignancies such as leukemia [58], it is interesting to speculate that patients with hematological malignancies other than leukemias may benefit from adding antiangiogenic therapy to standard treatments if CSCs could be identified in the malignant population of cells.

2.7. Effects of PPARγ and PPARγ Ligands on EC Functions and Angiogenesis

The endothelium releases a balance of bioactive factors that regulate vasoconstriction and relaxation to facilitate vascular homeostasis [179]. During homeostasis, the endothelium also inhibits platelet and leukocyte adhesion to the vascular surface and maintains the balance between prothrombotic and profibrinolytic activities. Several common conditions with a predisposition to atherosclerosis, including hypercholesterolemia, hypertension, diabetes, and stroke, are associated with endothelial dysfunction, leading to a proinflammatory and prothrombotic endothelium [180]. For more than a decade investigators have studied the effects of PPARγ ligands on EC functions with a particular interest in determining whether they could be used to inhibit cancer cell growth (reviewed in [25, 31, 181, 182]) and cancer-associated angiogenesis (reviewed in [23, 25, 31, 181184]). The functions that PPARγ ligands target during angiogenesis include induction of apoptosis, inhibition of EC proliferation, downregulation of proangiogenic factors, and as inhibitors of the inflammatory events that trigger and perpetuate pathological angiogenesis (Table 3). In addition to targeting tumor angiogenesis, PPARγ ligands have direct effects on cancer cells due to their ability to promote apoptosis, inhibit cell proliferation or induce differentiation [3, 71, 185188]. However, to date, disappointing results have been obtained in phase II clinical trials using the PPARγ ligand troglitazone to inhibit progression of treatment-refractory metastatic breast cancer [189], chemotherapy-resistant metastatic colorectal cancer [190], and prostate cancer [191]. In recent years, the focus has shifted from treating the tumor to targeting the signaling pathways that drive aberrant cell proliferation and survival and tumor-associated angiogenesis. Such targets have the potential for greater specificity together with reduced systemic toxicity [104].

Table 3
Effects of PPARγ agonists on endothelial cell function and angiogenesis.

2.8. Therapeutic Potential of PPARγ and PPARγ Ligands to Target Angiogenic Signaling Pathways in Treatment of Hematological Malignancies

It has been suggested that PPARγ functions as a tumor suppressor gene [204]; therefore, it is important to understand the complexity of signal transduction pathways and molecular players affected by PPARγ that promote tumor growth, cancer-associated angiogenesis, and metastasis. MM, a progressive hematological malignancy of plasma cells, remains largely incurable with survival averaging 3–5 years despite conventional and high-dose therapies; therefore, novel treatment approaches are desperately needed. MM is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence Jones protein (free monoclonal κ and λ light chains). Common clinical manifestations of MM are hypercalcemia, anemia, renal damage, increased susceptibility to bacterial or viral infection, and impaired production of normal immunoglobulins (http://www.themmrf.org/living-with-multiple-myeloma/newly-diagnosed-patients/what-is-multiple-myeloma/definition.html). Lytic lesions are often found in the bone including the pelvis, spine, ribs, and skull. Furthermore, neovascularization in bone marrow parallels disease progression of MM [205].

Our laboratory has shown that normal and malignant B cells, including MM, express PPARγ [206210], and that certain PPARγ ligands can induce apoptosis in MM cells [207, 208]. Because PPARγ ligands also have PPARγ-independent effects, we examined the functional consequences of PPARγ overexpression in human MM [207]. PPARγ overexpression in myeloma cells decreased cell proliferation, induced spontaneous apoptosis even in the absence of exogenous ligand, and enhanced their sensitivity to PPARγ ligand-induced apoptosis. Apoptosis was associated with the downregulation of anti-apoptotic proteins XIAP and Mcl-1 as well as induction of caspase-3 activity [207]. IL-6 mediates growth and survival of human myeloma cells through the MEK/MAPK and Jak/Stat signaling pathways, and IL-6 confers protection against dexamethasone-induced apoptosis via activation of the protein tyrosine phosphatase, SHP2 [211]. Binding of MM cells to BMSCs triggers expression of adhesive molecules and secretion of IL-6, promoting MM cell growth, survival, drug resistance, and migration. Furthermore, PPARγ overexpression-induced cell death of myeloma cells is not abrogated by coculture with BMSCs [207]. Overexpression of PPARγ in myeloma cells and BMSCs inhibited both basal and myeloma cell adhesion-induced IL-6 production by BMSCs. These results indicate that PPARγ negatively controls MM growth and viability, in part, through inhibition of IL-6 production by BMSCs [207]. Wang et al. [211] showed that myeloma cells express PPARγ and that the PPARγ agonists, 15d-PGJ2 and troglitazone, abolish IL-6-inducible myeloma cell proliferation and promote apoptosis in a PPARγ-dependent manner. These PPARγ agonists also reduced cell-cell adhesion between BMSCs and MM cells and overcame resistance to dexamethasone-mediated apoptosis in the MM.1R cell line through a PPARγ-dependent mechanism [212]. Taken together, the results of these studies demonstrate that PPARγ agonists can be used to inhibit IL-6-dependent crosstalk between myeloma cells and BMSCs [207, 211, 212], validating novel therapeutic strategies that target the tumor-stromal microenvironment.

Dankbar and colleagues [205] demonstrated that biologically active VEGF is expressed and secreted by myeloma cell lines and plasma cells isolated from the marrow of patients with MM. However, the myeloma cells did not express or only weakly expressed VEGFR1 and VEGFR2, indicating that autocrine VEGF signaling in MM is unlikely. In contrast, they demonstrated that BMSCs abundantly express VEGFR2 and that such expression could be stimulated in response to IL-6. In addition, exposure of BMSCs and microvascular ECs to VEGF induced a time- and dose-dependent increase in IL-6 secretion. They showed that IL-6-stimulated VEGF expression in and secretion from myeloma cell lines and in plasma cells purified from the marrow of patients with MM as well. Thus, this study confirms that paracrine interactions between myeloma and marrow stromal cells triggered by VEGF and IL-6 represent feasible signal transduction pathways to target for treatment of MM [205].

PPARγ ligands are known to inhibit or repress the activity of a number of transcription factors important in innate immunity, inflammation and cancer, including Stat3 and NF-κB [158, 159]; therefore, targeted inhibition of Stat3 and NF-κB activity with PPARγ agonists is a relevant avenue of investigation for new cancer therapeutics [213]. Wang and colleagues [211] showed that 15d-PGJ2 and troglitazone significantly inhibited Stat3 binding to its cognate response element and inhibited Stat3 binding to the promoters of c-MYC and MCL-1 thereby preventing transactivation of these Stat3 target genes. Whereas 15d-PGJ2 promotes direct binding of PPARγ to Stat3 forming a complex such that Stat3 is no longer capable of binding to the type II IL-6 response element on promoters of Stat3 target genes, troglitazone induces the redistribution of the corepressor NCoR/SMRT from PPARγ to Stat3, which leads to repression of Stat3 transactivation of target genes [211] (Figure 3(a)). In contrast, 15d-PGJ2 and troglitazone did not affect the expression of IL-6R or activation by phosphorylation of the downstream signaling molecules Jak/Stat3, MAPK, and PI3K/Akt in myeloma cells [211].

Figure 3
PPARγ agonists inhibit Stat3-mediated IL-6 gene expression in myeloma cells. Inactivation of IL-6-activated Stat3 by PPARγ agonists occurs in a PPARγ-dependent manner; however, the molecular mechanisms by which two distinct ...

PPARγ and its ligands effectively blocked IL-6 transcription and secretion from BMSCs that is induced in response to myeloma cell adhesion [212]. Such inhibition occurs through competition between PPARγ and NF-κB for the coactivator PGC-1, which is recruited from p65/p50 complexes by ligand-activated PPARγ (Figure 3(b)). Direct complex formation between PPARγ and C/EBPβ also prevents transactivation of the IL-6 promoter. The natural PPARγ ligand, 15d-PGJ2, has a PPARγ-independent effect on NF-κB by decreasing phosphorylation of IKK and IκB to prevent activation of NF-κB [212]. Prolonged treatment with the PPARγ ligand CDDO-Me inactivates Erk signaling in AML cells effectively inhibiting cell growth [214]. In vitro studies show that CDDO-Me inactivates Stat3, Src, and Akt; reduces expression of the c-MYC gene; promotes accumulation of cells in the G2-M phase of the cell cycle; and, abrogates invasive growth and induction of apoptosis of mammary cells [215]. Furthermore, mammary cell growth and lung metastases were completely eliminated in mice treated with CDDO-Me starting one day after tumor implantation; tumor growth was significantly inhibited when started after 5 days. Thus, CDDO-Me may have therapeutic potential for hematological malignancies and solid tumors through inactivation of Stat3 [215].

Bortezomib (Velcade, formerly PS-341) is a proteasome inhibitor that is used for antiangiogenic therapy in various cancers including MM [216]. Bortezomib targets myeloma cells and also inhibits the binding of myeloma cells to BMSCs. Furthermore, intravenous bortezomib, with or without dexamethasone, is well tolerated and effective in treating patients with relapsed or refractory MM [216]. Because bone marrow angiogenesis plays an important role in the pathogenesis and progression of MM and bortezomib inhibits angiogenesis, Roccaro and colleagues [217] tested the effects of bortezomib on the angiogenic phenotype of MM patient-derived ECs (MMECs). At clinically relevant concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells (HUVECs) in a dose-dependent and time-dependent manner. Bortezomib also inhibited angiogenesis as measured by capillary tube formation on Matrigel in vitro and in the chick embryo chorioallantoic membrane assay in vivo [217]. Furthermore, binding of drug sensitive MM cells (MM.1S) to MMECs triggered their proliferation, which was prevented by bortezomib. Bortezomib also triggered a dose-dependent inhibition of VEGF and IL-6 production by and secretion from MMECs and abrogated IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in MM [218]; gp130 is the signaling component of the high affinity IL-6R complex that activates Stat3. These data provide mechanistic insight on the antiangiogenic effects of bortezomib on MMECs in the bone marrow microenvironment [217] and support the concept that adding antiangiogenic agents as adjuvant or combination therapy with standard therapy would be more efficacious in treating patients with relapsed or refractory MM [219], and perhaps other hematological malignancies as well.

Although inhibiting IL-6 signaling through its high affinity receptor promotes apoptosis of MM cells when cocultured with BMSCs, some myeloma cells survive suggesting that the marrow microenvironment stimulates IL-6-independent pathways that exert a prosurvival effect [220]. BMSCs stimulate MAPK signaling in myeloma cells through IL-6R-independent mechanisms thereby circumventing the need for Stat3-mediated signaling in response to IL-6 for myeloma cell survival. Chatterjee et al. [220] went on to show that disruption of both the IL-6R/Stat3 and MAPK signaling pathways led to significantly more apoptosis of MM cell lines and primary MM cells even in the presence of BMSCs than singly inhibiting each signaling pathway. These results suggest that combined targeting of different and independently activated pathways is required to efficiently induce apoptosis of MM cells in the marrow microenvironment [220].

It should be kept in mind that anti-VEGF/VEGFR-targeted therapy could occur through a number of mechanistic pathways, such as direct inhibition of VEGF-induced angiogenesis or indirectly through mechanisms that inhibit expression of additional proangiogenic factors, promote apoptosis, or induce tumor dormancy [88, 221]. Rather than target the VEGF-signaling pathway, it may be possible to alter the phenotype of the angiogenic endothelium. The angiogenic EC phenotype is characterized by marked downregulation of CD36/fatty acid translocase (FAT) [222]. CD36 is a glycoprotein associated with normal and pathologic processes including scavenger receptor functions, lipid metabolism and fatty acid transport, cell adhesion, angiogenesis, modulation of inflammation, activation of TGF-β, atherosclerosis, diabetes, and cardiomyopathy [223]. PPARα regulates expression of CD36 in mouse liver and PPARγ regulates its expression in mouse adipose tissues [224, 225]. Furthermore, statins and PPARγ ligands together have an additive effect on upregulation of CD36 production by potentiating the transcription of the CD36 gene in monocytes [226]. CD36 is the cellular receptor for TSP-1 on microvascular endothelium and is necessary for its antiangiogenic, proapoptotic activity, making CD36 an attractive target for development of therapeutic agents [227].

Vascular endothelium expression of CD36 is sporadic however, with lower levels of expression in larger vessels [196, 228]. As discussed in Section 2.4, loss of endogenous inhibitors of angiogenesis in favor of proangiogenic factors produced by tumors leads to tumor-associated angiogenesis. A small peptide (ABT510) derived from TSP-1 type 1 repeats binds to CD36 and blocks tumorigenesis by reversing the “angiogenic switch” [229]. Huang et al. [196] demonstrated that 15d-PGJ2, troglitazone, and rosiglitazone potentiate the antitumor activity of AB510 in a CD36-dependent manner. Furthermore, these ligands upregulated EC expression of PPARγ and CD36 [43, 196], which likely leads to the synergistic inhibition of tumor-associated angiogenesis and induction of EC apoptosis in vivo [196]. Importantly, lower doses of PPARγ agonists could be used in combination with AB510 to significantly reduce tumor-associated angiogenesis and promote EC apoptosis. This study provides compelling evidence that PPARγ ligands could be useful as adjuvant or combination therapy in treatment of tumor angiogenesis.

Another important molecular mechanism to target for intervention of cancer progression in hematological malignancies is regulation of stromal matrix remodeling by proteases [193, 230]. PAI-1 production by ECs inhibits plasmin-mediated proteolytic degradation of the ECM. PPARγ ligands upregulate expression and release of PAI-1 from ECs [193], which would inhibit degradation of tumor-associated fibrin leading to EC migration, proliferation, and angiogenesis [231]. PPARγ ligands inhibit the adhesion of the myeloid leukemia HL-60 and K562 cells to the ECM as well as their invasion through Matrigel [230]. In addition, 15d-PGJ2 and troglitazone in both the HL-60 and K562 cell lines significantly inhibited MMP-9 and MMP-2 expression and proteolytic activities. The results of this study suggest that PPARγ ligands may inhibit leukemic cell adhesion to and invasion through the ECM as well as regulate angiogenesis by inhibiting matrix remodeling that favors cancer cell invasion and EC migration [230].

2.9. MicroRNAs and PPARγ Agonists in Hematological Malignancies

MicroRNAs (miRNAs) are short noncoding RNAs that function as negative regulators of the stability and/or translation of specific target mRNAs [232234]. Typically, miRNAs target a cluster of genes instead of one specific gene, and a single miRNA can have more than 100 targets [233, 235]. Regulation of gene expression by miRNAs is increasingly being accepted as a pivotal point in cell function, either in normal development or disease states (recently reviewed in [234, 236238]). Mature miRNAs derive from primary miRNA transcripts that are either transcribed from their own promoter regions [239] or processed introns spliced from pre-mRNAs [240]. Primary miRNAs are first processed in the nucleus by the RNase III endonuclease, Drosha, to form pre-miRNAs [241]. Pre-miRNAs are exported out of the nuclear compartment into the cytoplasm by exportin-5 [242]. Once in the cytoplasm, the pre-miRNA is further processed by another RNase III endonuclease, Dicer [243]. Finally, the mature miRNA is loaded onto the Argonaute (Ago) protein and incorporated into the ribonucleoprotein complex, RISC (RNA induced silencing complex) [244], which directs the miRNA to its target mRNA. Mature miRNAs primarily bind to transcripts through imperfect Watson-Crick base pairing to conserved miRNA binding sites in the 3′ untranslated region (UTR) of target mRNAs [234, 245]. The ability of miRNAs to regulate the expression of numerous genes at once often leads to pleiotropic effects and can modulate multiple cellular pathways.

There is growing evidence that dysfunctional expression of miRNAs is a common feature of malignancy in general and hematological malignancy in particular [233, 246]. Aberrant miRNAs have been documented in almost all hematological malignancies [247]. For example, Calin and colleagues [248] first implicated miRNAs in hematological malignancies when they demonstrated that miR-15 and miR-16 are frequently deleted or downregulated in CLL associated with deletions on chromosome 13q14. Deletion or downregulated expression of miR-15a and miR-16 on chromosome 13 is also found in MM cells [249]; deletion of chromosome 13 predicts significantly reduced survival in patients with MM [250]. In 2005, another group reported that the polycistronic precursor transcript of the miR-17~92 cluster, which encodes seven different miRNAs, is overexpressed in human B cell lymphomas and acts as an oncogene [251]. The miR-17~92 cluster is amplified and/or overexpressed in other hematological malignancies including AML [252, 253] and MM [246], as well as cancers of epithelial origin such as lung [254], thyroid [255], and hepatocellular [256] carcinomas. Overexpression of miR-21 occurs in MM [246, 257] and other cancers including glioblastoma [258] and breast cancer [259]. Thus, there is enormous hope that miRNA research will provide breakthroughs in the understanding of cancer pathogenesis and in the development of new prognostic markers [260].

Kuehbacher et al. [261] recently reviewed miRNAs that possess proangiogenic or antiangiogenic function. The miR-17~92 cluster, let-7f, and miR-27b posses proangiogenic functions, in part, by inhibiting expression of TSP-1 and CTGF. A role for miR-221 and miR-222 in blocking angiogenesis is suggested by their ability to inhibit EC migration, proliferation, and angiogenesis in vitro. In addition, miR-21 is implicated in the invasive and metastatic properties of colon and breast cancer cell lines by targeting multiple tumor suppressor genes, such as PTEN, TPM1, and MASPIN [259, 262, 263]. Moreover, miR-21 overexpression, which occurs in MM as discussed below, is associated with advanced clinical disease, lymph node metastasis and poor prognosis for overall survival in breast cancer [264]. The Sessa group demonstrated that a functional miRNA biogenesis pathway is required for angiogenesis [265, 266]. Inactivation of Dicer, the miRNA processing enzyme, impairs angiogenesis induced by multiple stimuli such as VEGF, and during tumorigenesis and wound healing [266]. VEGF also induces the expression of several proangiogenic miRNAs including the miR-17~92 cluster [266]. Furthermore, miR-130a functions in angiogenesis by inhibiting expression of two antiangiogenic homeobox transcription factors, HOXA5 and GAX [267].

Although the mechanisms regulating expression of miRNAs are only beginning to be understood [234, 236238, 268, 269], key regulators of the biosynthetic pathway are often abnormally expressed in hematological malignancies [270]. Recently, Löffler and colleagues [257] demonstrated that survival of IL-6-dependent MM cells involves Stat3-mediated induction of miR-21. Two bona fide IL-6 type II-response elements for Stat3 binding are located upstream of the miR-21 genes of various vertebrate species [257]. Stat3 regulates transactivation of several anti-apoptotic genes such as survivin, Bcl-2, and Mcl-1. Löffler et al. [257] suggest that Stat3 induction of miR-21 represents a “slow-acting yet long-lasting” survival stimulus to complement the immediate induction of anti-apoptotic proteins. The cancers in which miR-21 is overexpressed contain constitutively activated Stat3 for survival or growth [257]. These results suggest that miR-21 is important for the oncogenic potential of Stat3 in the pathogenesis of MM and other malignancies. IL-6-mediated activation of Stat3 is also important for transformation of nonmalignant breast epithelial cells to self-renewing mammospheres that contain CSCs [271]. Inflammation in cancer leads to elevated IL-6 production by two mechanisms: Src-mediated activation of NF-κB leading to transactivation of the IL-6 gene, and rapid degradation of let-7 miRNA, which is a direct inhibitor of IL-6 expression [271]. Let-7 is downregulated in some cancers including Burkitt lymphoma [272] thereby leading to elevated IL-6 production, likely due to activation of the oncogenic NF-κB-IL-6-Stat3 inflammatory pathway. In that the PPARγ agonist CDDO-Me inactivates Src and Stat3 in cancer cells [215], further investigation of the efficacy of various PPARγ ligands as anticancer agents is certainly warranted.

Recently, Roccaro and colleagues [249] identified a multiple myeloma-specific miRNA signature characterized by downexpression of miR-15a and miR-16 and overexpression of miR-222, miR-221, miR-382, miR-181a, and miR-181b in bone marrow-derived CD138+ MM cells. Both miR-15a and miR-16 regulate proliferation and growth of plasma cells by inhibiting Akt and MAPK cell survival signaling pathways. However, both miR-15a and miR-16 are deleted on chromosome 13 associated with MM [249] thereby preventing normal repression of cell proliferation during cancer progression. Pichiorri et al. [246] also identified an miRNA signature associated with MM pathogenesis. Overexpression of miR-21, the miR-106b~25 cluster, and miR-181a and miR-181b was found in MM and monoclonal gammopathy of undetermined significance (MGUS) samples. On the other hand, selective upregulation of miR-32 and the miR-17~92 cluster was identified only in MM cells. Expression of suppressor of cytokine signaling (SOCS)-1, involved in negative feedback regulation of Jak/Stat signaling, is downregulated by miR-19a and miR-19b thereby leading to sustained IL-6-mediated MM cell proliferation [246]. Furthermore, miR-19a, miR-19b, miR-181a, and miR-181b antagonists suppress human MM tumor cell growth in nude mice, suggesting that miRNAs that modulate the expression of proteins critical to myeloma pathogenesis, including the IL-6-regulated Stat3 pathway, are potential targets for development of new therapeutic strategies for treatment [246].

The Stat3-regulated gene, HIF-1α, is constitutively expressed under normoxia in CLL B cells, most likely as a result of low production of pVHL, which is responsible for HIF-1α degradation. Ghosh and colleagues [273] demonstrated that overexpression of miR-92 in CLL B cells targets the VHL transcript to repress its translation (Figure 4). Furthermore, stabilized HIF-1α forms an active complex with the transcriptional coactivator p300 and activated Stat3 on the VEGF promoter, which likely explains the anomalous autocrine VEGF secretion from CLL B cells [273]. In that PPARγ agonists inhibit the IL-6-regulated Stat3 signaling cascade, a role for PPARγ agonists in regulating expression of miRNAs critical to the pathogenesis of hematological malignancies may be an important avenue of future scientific investigations.

Figure 4
Autocrine production of VEGF in CLL B cells is regulated by miRNA-92-1 inhibition of pVHL production. Expression of high levels of VEGF by tumor cells is critical to promote and sustain the angiogenesis needed for cancer progression. Under normal ...

Recently, miRNAs have emerged as epigenetic regulators of metabolism and energy homeostasis [274]. It is clear that there is an obesity epidemic in the United States [275]. Increased body weight is associated with increased mortality for most all types of cancers including hematological malignancies [276]. Additional studies have confirmed that obesity puts patients at a moderate increased risk of developing MM [276279], and that this risk may be higher in women than men [279]. An important link between obesity and MM is elevated expression of IL-6 in adipose tissue [280] and bone marrow [207], which also leads to elevations in circulating IL-6. Lin et al. [274] demonstrated that the miR-27 gene family is downregulated during adipogenic differentiation. Furthermore, overexpression of miR-27 specifically inhibits adipocyte formation and expression of PPARγ and C/EBPα, the two master transcriptional regulators of adipogenesis. Although PPARγ and C/EBPα mRNA and protein levels were markedly reduced by miR-27a or miR-27b, it was not a direct miRNA effect [274]. Expression of miR-27 is increased in fat tissue of obese mice and is regulated by hypoxia, an important extracellular stress associated with both obesity and cancer. During adipogenesis the expression of miR-27b, an important regulator of angiogenesis, is downregulated in human adipogenic stem cells, and PPARγ mRNA expression increases concomitantly with decreasing miR-27b expression [281]. Both miR-27a and miR-27b directly bind RXRα mRNA and regulate RXRα translation in rat hepatic stellate cells [282]. It is well known that RXRα heterodimerizes with PPARγ to activate numerous genes required for adipogenesis and energy metabolism. These data suggest that miR-27 represents a new class of adipogenic inhibitors and their downregulation may play a role in the pathological development of obesity [274]. Furthermore, in that PPARγ is a master regulator of adipogenesis and target of insulin sensitizing drugs, it is reasonable to consider that the beneficial effects of PPARγ agonists in cancer treatment may be exerted through regulation of energy homeostasis, at least in part, by modulation of miRNA expression. Indeed, the anticarcinogenic activity of one of the triterpenoids is due to repression of oncogenic miR-27a [283].

All known forms of the human PPARγ mRNA contain numerous miRNA binding sites in the 3′UTR as predicted through different bioinformatic algorithm databases (TargetScan [284], miRanda [285], PicTar [286]). The miRNA binding sites for miR-27a/b, miR-130a/b, miR-301, miR-34a/b in the PPARγ 3′UTR are conserved in human, chimp, mouse, and rat. Notably, two conserved binding sites for miRNAs in the PPARγ  3′UTR are for miR-27b and miR-130a that have angiogenic or proliferative functions. It would be interesting to determine whether these miRNAs suppress PPARγ function during angiogenesis and/or tumor growth. This could lead to identification of novel targets that may induce PPARγ expression leading to the anticancer functions of cell differentiation and loss of proliferation. However, a role for PPARγ agonists in miRNA-based therapeutic strategies to treat cancer awaits further clarification by new research endeavors.

3. Anticancer Role of PPARγ Agonists as Adjuvant or Combination Therapy in Hematological Malignancies of the Eyes

3.1. Ocular Hematological Malignancy

Ocular lymphoma is relatively uncommon, accounting for 5–10% of all extranodal lymphomas [288]. However, it is one of the most common orbital malignancies and it is increasing in incidence because of its association with the acquired immunodeficiency syndrome (AIDS) [289]. Ocular lymphoma can be divided into intraocular and adnexal disorders, the former, including malignant lymphoid cells, invade the retina, vitreous body, or optic nerve head; the latter include conditions affecting the eyelid, the conjunctiva, the lacrimal gland, and the orbit [290]. Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma. It is usually a large B-cell NHL [291]. PIOL typically presents as a vitritis that is unresponsive to corticosteroid therapy. Diagnosis of PIOL requires pathologic confirmation of malignant cells in specimens of the cerebrospinal fluid, vitreous, or chorioretinal biopsies. The extranodal marginal zone lymphoma (mucosaassociated lymphoid tissue lymphoma) is the dominant lymphoma subtype in the orbit and ocular adnexa. Extranodal marginal zone lymphoma is considered to be the neoplastic counterpart of the marginal zone cells in reactive follicles [292]. Although optimal therapy has yet to be determined [293], it is believed that PIOL should be treated with a combination of chemotherapy and radiation.

Ocular involvement is common in patients with acute leukemia and has been described in up to half of patients at the time of diagnosis [294]. Eye involvement may be due to leukemic infiltration of various ocular tissues or as a result of one of the secondary complications of the disease [295]. These complications include anemia, thrombocytopenia, and leukostasis, which can lead to retinal hemorrhaging and ischemia [294]. Hemorrhaging in the retina is the most striking feature of ocular leukemia. Furthermore, retinal microaneurysms, capillary closure, and neovascularization have been documented in individuals with chronic leukemia [296, 297]. The treatments include chemotherapy, radiation, or bone marrow transplantation. Ocular findings may be the first manifestation of MM [298]. It may also occur as one of the extramedullary manifestations of the disease or as the first sign of insufficient chemotherapy. MM causes ocular pathology by direct infiltration or as extramedullary plasmacytomas resulting in the displacement or compression of tissues causing hyperviscosity syndrome and immunoglobulin light chain deposition in ocular tissues. Virtually any ocular structure can be affected, including the conjunctiva, cornea, sclera, lens, retina, optic nerve, lacrimal glands, and orbit [298] (Figure 5).

Figure 5
PPARγ is broadly expressed in the eye providing a pharmacological target for treating ocular angiogenesis. PPARγ expression is found in the retina including RPE cells, REC, pericytes [287], and ganglion cells. In the cornea, ...

3.2. Ocular Neovascularization

Ocular angiogenesis or ocular neovascularization, the abnormal growth of blood vessels in the eye, is the hallmark of the vast majority of eye diseases that cause a catastrophic loss of vision including diabetic retinopathy, AMD, retinopathy of prematurity, and vein occlusion retinopathy [299, 300]. The new vessels may grow into nearly all mature ocular tissue and affect the cornea, iris, retina, and optic disk [301]. They are structurally weak, both leaking fluid and lacking structural integrity. Moreover, the resultant hemorrhage, exudate, and accompanying fibrosis often cause blindness [302].

The cornea is a highly organized transparent tissue located in the anterior part of the eye and it is normally avascular. However, under certain conditions, such as corneal trauma, chemical burns, infection, and inflammation, the development of new blood vessels starts from the vessel of the limbal area (Figure 5). Newly formed blood vessels cover the corneal surface [303], which can lead to severe or permanent visual impairment [302]. The choroid is the layer of blood vessels and connective tissue between the sclera and retina and supplies nutrients to the inner parts of the eye [304]. Choroidal neovascularization (CNV) is associated with many other conditions, such as AMD, inflammatory, infectious, degenerative, hereditary, congenital disorders, tumors, trauma, and a few miscellaneous ocular disorders [302]. In CNV, neovascular channels grow from the choroidal vasculature and extend into the subretinal space leading to local tissue damage. Activation and migration of choroidal ECs (CECs) and retinal pigment epithelial (RPE) cells into the CNV membranes play an important role in the development of the lesion [305]. The mammalian retina is a light sensitive tissue lining the inner surface of the eye, which is composed of multiple cell-types organized within defined layers. It has a dual blood supply from the central retinal artery and the choroidal blood vascular system [304]. Neovascularization of the retina is a critical part of the disease process associated with retinopathy in diabetes, prematurity, and sickle cell disease [302].

3.3. Expression of PPARγ in the Eye and Effects on Ocular Neovascularization

PPARγ expression in the mammalian eye has been reported prominently in retina [306, 307] including RPE cells [194, 308, 309], retinal capillary ECs (REC) [310, 311], retinal pericytes [287], and retinal ganglion cells [312]. PPARγ is most prominently localized in the epithelial and endothelial layers of the cornea [198]. PPARγ is also found in CECs [194] and in orbital fibroblasts [313, 314]. The broad expression of PPARγ in the eye provides a pharmacological target for treating ocular angiogenesis.

In vivo alkali-burned mouse cornea experiments showed that neovascularization and scar formation are suppressed by introduction of PPARγ gene expression. PPARγ overexpression suppressed monocyte/macrophage invasion and suppressed the generation of myofibroblasts, as well as upregulation of inflammation/scarring-related growth factors (TGF-β, CTGF, and VEGF) and MMPs in a healing cornea. In vitro experiments showed that overexpression of PPARγ suppressed epithelial cell expression of MMP-2/-9 and TGF-β1, inhibited cell migration, and suppressed myofibroblast generation upon exposure to TGF-β1. Thus, adenoviral-driven expression of the PPARγ gene led to inhibition of the anti-inflammatory and antifibrogenic responses induced in an alkali-burned mouse cornea, and also inhibited activation of ocular fibroblasts and macrophages in vitro [12]. In a VEGF-induced neovascular rat cornea model, intrastromal implantation of the PPARγ ligands pioglitazone [198] or 15d-PGJ2 [22] resulted in decreasing MVD, indicating inhibition of ocular angiogenesis. Furthermore, systemic oral administration of rosiglitazone and troglitazone significantly inhibits vessel growth in a dose-dependent fashion in a model of FGF-2-induced mouse corneal neovascularization [195].

PPARγ ligands troglitazone and rosiglitazone inhibit VEGF-induced cell proliferation and migration in bovine CECs and human RPE cells in vitro. Troglitazone also inhibits VEGF-induced tube formation (neovascularization) of CECs [194]. Troglitazone pretreatment can significantly prevent TGF-β-induced epithelial-mesenchymal transition of human RPE cells, and retard cell migration [315]. In vivo, laser photocoagulation induced CNV was markedly inhibited by intravitreal injection of troglitazone in rat and monkey eyes. The lesions showed significantly less fluorescein leakage and were histologically thinner in the troglitazone-treated animals without apparent adverse effects in the adjacent retina or in control eyes [194], indicating that the PPARγ ligands are logical for therapy to suppress vascular permeability in the eye.

PPARγ agonists, troglitazone, rosiglitazone, Pioglitazone, RWJ241947, and 15d-PGJ2, inhibit proliferation of human REC and pericytes in vitro through a PPARγ-independent pathway [316]. TZDs downregulate cyclin E (S-phase cyclin) and cyclin A (G2/M-phase cyclin) resulting in cell cycle arrest [316]. Troglitazone and rosiglitazone inhibit VEGF-induced proliferation and tube formation by bovine REC in collagen gels, and inhibit VEGF-induced REC migration in a dose-dependent manner [311]. Retinal angiogenesis is induced in newborn mice by oxygen-induced ischemic injury; however, intravitreal injection of troglitazone or rosiglitazone markedly reduced development of retinal neovascular tissue [311]. In the chick chorioallantoic membrane model of angiogenesis, pioglitazone and rosiglitazone significantly inhibit EC migration as well as the proangiogenic effects of FGF-2 and VEGF [27]. Rosiglitazone may delay the onset of proliferative diabetic retinopathy, possibly because of its antiangiogenic activity [317].

Taken together, these studies demonstrate that PPARγ ligands are potent inhibitors of angiogenesis in vivo and in vitro, and suggest that PPARγ may be an important molecular target for inhibiting angiogenesis. The use of PPARγ ligands to prevent pathological angiogenesis holds great potential as a novel therapeutic for neovascularized eye diseases. It may also apply to other neovascularization-related diseases, including hematological malignancies of the eye. However, future clinical investigations should consider analysis of the potential benefits of PPARγ agonist treatment along with ongoing evaluation of potential cardiac risk in studies where the risk-benefit profiles are deemed appropriate [317].

4. The Paradox of PPARγ as a Molecular Target in Anticancer Therapy

The aforementioned studies examining the role of PPARγ ligands for treatment of hematological, ocular, and solid malignancies is by no means a complete review of the available literature. The list of off-target effects of PPARγ agonists continues to grow [51]. Furthermore, many of the published studies suggesting that PPARγ ligands exert antitumor properties did not determine whether the effects required ligand activation of the PPARγ transcription factor per se (Table 3). Many human cancer cell lines express high levels of PPARγ, which when treated with high concentrations of TZDs, undergo cell cycle arrest, apoptosis, or differentiation, suggesting a link between PPARγ signaling and their antitumor activities. In contrast, mounting evidence refutes the dependence of the antitumor effects of TZDs on PPARγ activation [25, 51, 318]. Of note, the off-target effects of PPARγ ligands usually occur at much higher concentrations than those required for ligand-dependent PPARγ effects, and there is no correlation between the expression levels of PPARγ in cancer cells and their sensitivity to TZDs [25, 51, 318]. Indeed, PPARγ agonists exert pleiotropic effects on signal transduction pathways involved in cell proliferation, survival and differentiation [25, 51, 71, 188, 318322] (Table 3 and Figure 6).

Figure 6
Direct and indirect effects of PPARγ agonists on tumor and stromal cells. “Off-target” (PPARγ-independent) effects of PPARγ agonists frequently occur when the agonists are used at high concentrations (much ...

Currently, two PPARγ agonists belonging to the TZDs remain on the market, rosiglitazone (Avandia) and pioglitazone (Actos). In 2000, troglitazone (Resulin) was removed from the market due to severe hepatotoxicity. Moreover, the incidence of delayed drug-induced liver injury that progresses after discontinuation of drug therapy, and whether such injury is specific to just troglitazone or TZDs as a class of drugs, remains unknown [323]. Additional adverse effects associated with TZDs used for insulin sensitizing therapy include edema, weight gain, macular edema, and heart failure [323, 324]. TZDs may cause hypoglycemia when combined with other antidiabetic drugs as well as decrease hematocrit and hemoglobin levels. Furthermore, an increased risk of bone fracture is linked to TZD therapy [324, 325]. When considering the use of PPARγ agonists as adjuvant or combination therapy in hematological malignancies, it will be important to design appropriate preclinical studies that assess the severity of these side effects in the context of each type of cancer. For example, increased edema is associated with increased vascular permeability. The loss of endothelial barrier integrity leads to increased vascular permeability, enhanced transendothelial migration, and metastatic spread of cancer cells [75]. Thus, the potential for TZDs to promote rather than prevent the metastatic spread of cancer should be considered. The malignant proliferation of plasma cells in MM produces skeletal lesions leading to bone pain and pathologic fractures such as vertebral compressions [326]. In that TZDs are associated with increased risk of bone fractures; the use of TZDs for treatment of MM must be evaluated as well.

Evidence suggesting that the effects of TZDs on improving endothelial-dependent vascular function and decreasing inflammatory biomarkers independently of insulin-sensitizing effects came from studies reporting the effects of TZDs in diabetic and nondiabetic individuals with atherosclerosis [327329]. In general, PPARγ agonists inhibit tumor-associated angiogenesis by inhibiting FGF-2- and VEGF-induced EC growth, invasion and migration in vitro and in vivo [27, 192], downregulate expression of VEGF by tumor cells [195, 199] and VEGFRs by EC [32], and decrease tumor-associated MVD [24, 32, 198] and EC tube formation [202], measures of angiogenesis in vivo and in vitro, respectively. TZDs inhibit pathological angiogenesis associated with diabetic retinopathy [287, 317], as well as choroidal and retinal neovascularization [194, 198, 311], and suppress primary tumor growth and metastasis by inhibiting angiogenesis [35] (Table 3). Interestingly, in contrast to these reports, TZDs increase VEGF expression in human vascular smooth muscle cells [330] and promote angiogenesis after ischemia [331]. Additional reports suggest that PPARγ ligands are capable of promoting angiogenesis by inducing VEGF expression [28, 30, 203].

Huang and colleagues [30] have suggested that pioglitazone has different effects on pathological angiogenesis compared to ischemia-induced collateral vessel growth [332]. TZDs promote differentiation of EPCs/APCs towards the endothelial lineage [197, 200, 201], consistent with the idea that PPARγ ligands have differential effects on angiogenesis needed for restoration of homeostasis in cardiovascular disease or diabetes compared to pathological angiogenesis associated with cancer progression. The role of PPARγ and its ligands in inhibiting or promoting angiogenesis is likely context dependent (Section 2.7 and Table 3) [30, 332]; thus, the use of PPARγ ligands alone or in addition to antiangiogenic agents for treatment of hematological malignancies will require a better understanding of the effects of PPARγ agonists on EC function during pathological angiogenesis.

Many studies have demonstrated beneficial effects of PPARγ agonists on atherosclerosis and ischemia reperfusion injury by reducing inflammation, preventing restenosis after percutaneous coronary intervention, and in some instances, preventing myocardial infarction and cardiovascular death. Recently, however, a number of review articles have discussed the “rosiglitazone debate” about whether taking rosiglitazone puts patients at a higher overall risk of cardiovascular death. The higher risk is based on findings derived from meta-analyses of existing clinical trial data, the release of FDA safety warnings that rosiglitazone increases cardiac ischemic risk, manufacturer updates on TZD labels with a black-box warning for heart failure, as well as warnings and precautions about coadministration of rosiglitazone with nitrate or insulin [333336]. TZDs are known to induce salt and water retention, which exacerbate the risk of congestive heart failure in patients with type 2 diabetes. Rosiglitazone is a more potent agonist of PPARγ than pioglitazone, thus increased fluid retention and salt imbalance may explain the higher risk of heart failure with this TZD [336]. However, even though treatment with rosiglitazone may, in general, be associated with a higher incidence of cardiovascular events, some studies suggest that there is no increase in all-cause or cardiovascular mortality observed with rosiglitazone treatment [333, 335]. Clearly, prospective randomized trials need to include outcomes measures to determine whether the TZDs and other such compounds under development put patients at a higher overall risk of cardiovascular death.

As cancer treatments improve, the number of patients who reach the 5-year benchmark of disease-free survival continues to grow. However, adverse effects of anticancer therapy may confound long-term survival. For example, as methods for detecting and treating breast cancer improve, survival of breast cancer patients is increasing but the side effects of adjuvant therapy, including cardiotoxicity, remain clinically important [337]. Agents commonly used for the treatment of breast cancer, including anthracyclines and trastuzumab, have been associated with cardiotoxicity [338], which ranges from subclinical to life-threatening pathology and even fatal results [339]. Imatinib (Gleevec) inhibits the continuously active tyrosine kinase, Bcr-Abl, which results from the translocation of chromosomes 9 and 22 and is effective for the treatment of CML as well as ALL; however, cardiotoxicity is a potentially serious side effect of this drug as well [340]. In that the TZD class of PPARγ agonists is associated with adverse cardiovascular events, additional studies on the efficacy of PPARγ agonists and other lead compounds as adjuvant or combination therapy to treat cancer should be designed to look at the cardiovascular risks and benefits in addition to their efficacy in treating the primary disease.

5. Conclusions

The goal to find a cure for all types of cancer is a major initiative of both public and private grant funding institutions and foundations. Thus, forwarding thinking researchers are exploring strategies to identify molecular expression profiles of cancer subtypes and CSCs, to optimize tumor imaging methods to identify cancer micrometastases, as well as to develop more-specific, less toxic drugs through medicinal chemistry to provide tailored therapy to treat and cure cancer in individual patients. However, metastatic disease remains the major cause of morbidity and mortality in both solid tumors and hematological malignancies. Because tumor-associated angiogenesis is critical for cancer progression and metastatic disease, the initiative to identify molecular targets and new or improved chemotherapeutic or biologic agents to inhibit angiogenesis is a high priority area of research in cancer medicine.

Specific areas of research where PPARγ agonists may be further examined for efficacy in treatment of angiogenesis in hematological malignancies as well as comorbidities that affect quality of life for long-term cancer survivors include signal transduction pathways (e.g., Jak/Stat, PI3K/Akt, PTEN, mTOR) [181, 341, 342], aberrant/oncogenic miRNAs [246, 257, 261, 283, 343345], targeting CSCs while sparing normal hematopoietic stem cells, and correcting dysregulated metabolic pathways due to drug side effects such as hyperglycemia, hypertension, gastrointestinal toxicity, coagulation disorders, and depression associated with the neurotoxicity of chemotherapeutic drugs [341, 346348]. Moreover, limitations in the experimental design of published studies should be carefully evaluated. A significant number of studies continue to use troglitazone as a PPARγ agonist despite its having been pulled from the marketplace due to hepatotoxicity. In vitro experiments examining the efficacies of candidate drugs as inhibitors of angiogenesis need to reflect the complexity of the tumor microenvironment in keeping with the in vivo context. For example, large vessel ECs isolated from the veins of human umbilical cords (HUVECs) are frequently used to study angiogenesis by capillary tube formation in 2D-matrix configurations in vitro; however, in vivo tumor-associated angiogenesis occurs in a complex environment composed of multiple cell types including microvessel ECs and matrix constituents in a 3D-configuration. It will also be important to determine whether the therapeutic effects of PPARγ agonists are due to off-target interactions. In conclusion, we hope that this paper has provided a conceptual framework upon which future studies will be designed to unravel the pleiotropic effects of PPARγ in the context of the stromal microenvironment during tumor angiogenesis, growth and metastasis in hematological malignancies.

Acknowledgments

Grant Support. National Institutes of Health; EY-017123, ES-01247, DE-011390, HL-078603, and T32 DE007202; Research to Prevent Blindness, Rochester Eye and Tissue Bank; a Grant-in-Aid (0655897T) from the American Heart Association Founders Affiliate. Dedication. The first author would like to dedicate this paper to her loving father, Clifford John Simpson, who died from multiple myeloma on December 6, 2008 at the age of 95 years and 3 months old, and to his Doctor, Jane L. Liesveld, M.D., who treated the man first then the disease.

Abbreviations

15d- PGJ2:
15-deoxy-Δ-12-14-prostaglandin J2
Ago:
Argonaute
AIDS:
Acquired immunodeficiency syndrome
Akt/PKB:
v-akt murine thymoma viral oncogene homolog/protein kinase B
AMD:
Age-related macular degeneration
AML:
Acute myeloid leukemia
ANGPTL4:
Angiopoietin-like factor-4
AP-1:
Activator protein 1
APC:
Angiogenic precursor cell
APL:
Acute promyelocytic leukemia
ARNT:
Aryl hydrocarbon nuclear translocator
B-ALL:
B type acute lymphoblastic leukemia
Bcr-Abl:
Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1/Philadelphia chromosome
BMSC:
Bone marrow stromal cell
C/EBP:
CAAT enhancer binding protein
CAM:
Chorioallantoic membrane
CDDO-Im:
CDDO C-28 imidazole
CDDO-Me:
CDDO C-28 methyl ester derivative
CDDO:
2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid
CEC:
Choroidal endothelial cell
CLL:
Chronic lymphocytic leukemia
CML:
Chronic myeloid leukemia
CNV:
Choroidal neovascularization
CSC:
Cancer stem cell
CTCL:
Cutaneous T cell lymphoma
CTGF:
Connective tissue growth factor
DIM #34:
1,1-bis[3′-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane
DLBCL:
Diffuse large B cell lymphoma
EC:
Endothelial cell
ECM:
Extracellular matrix
EPC:
Endothelial precursor cell
FAT:
Fatty acid translocase
FGF-2:
Fibroblast growth factor-2
gp130:
Glycoprotein 130
HIF:
Hypoxia inducible factor
HSF:
Hepatocyte stimulatory factor
HSPG:
Heparan sulfate proteoglycan
HUVEC:
Human umbilical vein endothelial cell
IGF-1:
Insulin-like growth factor
IκB:
Inhibitor of κB
LDL:
Low density lipoprotein
MAPK:
Mitogen-activated protein kinase
MASPIN:
Mammary serine protease inhibitor (tumor suppressor gene)
MCP-1/CCL2:
Macrophage chemotactic protein
MIF:
Macrophage inhibitory factor
miRNA:
MicroRNA
MM:
Multiple myeloma
MMEC:
Multiple myeloma derived endothelial cell
MMP:
Matrix metalloproteinase
mTOR:
Mammalian target of the rapamycin
MVD:
Microvessel density
NF-κB:
Nuclear factor κB
NHL:
Non-Hodgkin lymphoma
NOD/SCID:
Nonobese diabetic/severe combined immune deficiency
NRP:
Neuropilin
p300/CBP:
Transcriptional coactivator protein/cAMP-response element-binding protein (CREB) binding protein
PAI:
Plasminogen activator inhibitor
PDGF:
Platelet derived growth factor
PGC-1:
PPARγ coactivator-1
PI3K:
Phosphatidylinositol 3-kinase
PIOL:
Primary intraocular lymphoma
PLGF:
Placenta growth factor
PPAR:
Peroxisome proliferator-activated receptor
PPRE:
PPARγ response element
PTEN:
Phosphatase and tensin homolog (tumor suppressor gene)
pVHL:
Protein von Hippel-Lindau
REC:
Retinal capillary endothelial cell
RISC:
RNA induced silencing complex
RPE:
Retinal pigmented epithelial
SBE:
Stat3 Binding Element
SMRT/NCoR:
Silencing mediator for retinoid and thyroid hormone receptors/nuclear receptor corepressor
SOCS:
Suppressor of cytokine signaling
Src:
v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian); aka, p60-Src
STAT:
Signal transducer and activator of transcription
TGF-α/β:
Transforming growth factor
TIMP:
Tissue inhibitor of metalloproteases
TNF-α:
Tumor necrosis factor
TPM1:
Tropomysin 1 (tumor suppressor gene)
Tro:
Troglitazone
TSP:
Thrombospondin
TZDs:
Thiazolidinediones
UTR:
Untranslated region
VEGF:
Vascular endothelial growth factor
VEGFR:
VEGF receptor
VPF:
Vascular permeability factor.

References

1. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor super-family: the second decade. Cell. 1995;83(6):835–839. [PubMed]
2. Lazar MA. PPARγ, 10 years later. Biochimie. 2005;87(1):9–13. [PubMed]
3. Garcia-Bates TM, Lehmann GM, Simpson-Haidaris PJ, Bernstein SH, Sime PJ, Phipps RP. Role of peroxisome proliferator-activated receptor gamma and its ligands in the treatment of hematological malignancies. PPAR Research. 2008;2008:18 pages. Article ID 834612. [PMC free article] [PubMed]
4. Goldenberg I, Benderly M, Goldbourt U. Update on the use of fibrates: focus on bezafibrate. Vascular Health and Risk Management. 2008;4(1):131–141. [PMC free article] [PubMed]
5. Sharma AM, Staels B. Review: peroxisome proliferator-activated receptor γ and adipose tissue—understanding obesity-related changes in regulation of lipid and glucose metabolism. Journal of Clinical Endocrinology and Metabolism. 2007;92(2):386–395. [PubMed]
6. Evans JL, Lin JJ, Goldfine ID. Novel approach to treat insulin resistance, type 2 diabetes, and the metabolic syndrome: simultaneous activation of PPARα, PPARγ, and PPARδ Current Diabetes Reviews. 2005;1(3):299–307. [PubMed]
7. Meerarani P, Badimon JJ, Zias E, Fuster V, Moreno PR. Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. Current Molecular Medicine. 2006;6(5):501–514. [PubMed]
8. Palomo I, Alarcon M, Moore-Carrasco R, Argiles JM. Hemostasis alterations in metabolic syndrome (review) International Journal of Molecular Medicine. 2006;18(5):969–974. [PubMed]
9. Staels B. PPAR agonists and the metabolic syndrome. Therapie. 2007;62(4):319–326. [PubMed]
10. Jay MA, Ren J. Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Current Diabetes Reviews. 2007;3(1):33–39. [PubMed]
11. Rosenson RS. Fenofibrate: treatment of hyperlipidemia and beyond. Expert Review of Cardiovascular Therapy. 2008;6(10):1319–1330. [PubMed]
12. Saika S, Yamanaka O, Okada Y, et al. Effect of overexpression of PPARγ on the healing process of corneal alkali burn in mice. American Journal of Physiology. 2007;293(1):C75–C86. [PubMed]
13. Michalik L, Desvergne B, Tan NS, et al. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)α and PPARβ mutant mice. Journal of Cell Biology. 2001;154(4):799–814. [PMC free article] [PubMed]
14. Zhang R, Zheng F. PPAR-γ and aging: one link through klotho? Kidney International. 2008;74(6):702–704. [PubMed]
15. Sulistio MS, Zion A, Thukral N, Chilton R. PPARγ agonists and coronary atherosclerosis. Current Atherosclerosis Reports. 2008;10(2):134–141. [PubMed]
16. Villacorta L, Schopfer FJ, Zhang J, Freeman BA, Chen YE. PPARγ and its ligands: therapeutic implications in cardiovascular disease. Clinical Science. 2009;116(3):205–218. [PMC free article] [PubMed]
17. Duez H, Fruchart J-C, Staels B. PPARs in inflammation, atherosclerosis and thrombosis. Journal of Cardiovascular Risk. 2001;8(4):187–194. [PubMed]
18. Ray DM, Spinelli SL, O’Brien JJ, Blumberg N, Phipps RP. Platelets as a novel target for PPARγ ligands: implications for inflammation, diabetes, and cardiovascular disease. BioDrugs. 2006;20(4):231–241. [PubMed]
19. Spinelli SL, O’Brien JJ, Bancos S, et al. The PPAR-platelet connection: modulators of inflammation and potential cardiovascular effects. PPAR Research. 2008;2008:16 pages. Article ID 328172. [PMC free article] [PubMed]
20. Akbiyik F, Ray DM, Gettings KF, Blumberg N, Francis CW, Phipps RP. Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes. Blood. 2004;104(5):1361–1368. [PubMed]
21. Cao Z, Zhou Y. Thiazolidinediones may be effective in the prevention of stent thrombosis with DES. Medical Hypotheses. 2008;70(2):329–332. [PubMed]
22. Xin X, Yang S, Kowalski J, Gerritsen ME. Peroxisome proliferator-activated receptor γ ligands are potent inhibitors of angiogenesis in vitro and in vivo. Journal of Biological Chemistry. 1999;274(13):9116–9121. [PubMed]
23. Margeli A, Kouraklis G, Theocharis S. Peroxisome proliferator activated receptor-γ (PPAR-γ) ligands and angiogenesis. Angiogenesis. 2003;6(3):165–169. [PubMed]
24. Keshamouni VG, Arenberg DA, Reddy RC, Newstead MJ, Anthwal S, Standiford TJ. PPAR-γ activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neoplasia. 2005;7(3):294–301. [PMC free article] [PubMed]
25. Panigrahy D, Huang S, Kieran MW, Kaipainen A. PPARγ as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biology and Therapy. 2005;4(7):687–693. [PubMed]
26. Piqueras L, Reynolds AR, Hodivala-Dilke KM, et al. Activation of PPARβ/δ induces endothelial cell proliferation and angiogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27(1):63–69. [PubMed]
27. Aljada A, O’Connor L, Fu Y-Y, Mousa SA. PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis. 2008;11(4):361–367. [PubMed]
28. Biscetti F, Gaetani E, Flex A, et al. Selective activation of peroxisome proliferator-activated receptor (PPAR)α and PPARγ induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism. Diabetes. 2008;57(5):1394–1404. [PubMed]
29. Fraisl P, Baes M, Carmeliet P. Hungry for blood vessels: linking metabolism and angiogenesis. Developmental Cell. 2008;14(3):313–314. [PubMed]
30. Huang P-H, Sata M, Nishimatsu H, Sumi M, Hirata Y, Nagai R. Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice. Biomedicine and Pharmacotherapy. 2008;62(1):46–52. [PubMed]
31. Kim E-H, Surh Y-J. The role of 15-deoxy-Δ12,14-prostaglandin J2, an endogenous ligand of peroxisome proliferator-activated receptor γ, in tumor angiogenesis. Biochemical Pharmacology. 2008;76(11):1544–1553. [PubMed]
32. Dong Y-W, Wang X-P, Wu K. Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition. World Journal of Gastroenterology. 2009;15(4):441–448. [PMC free article] [PubMed]
33. Panigrahy D, Kaipainen A, Huang S, et al. PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(3):985–990. [PubMed]
34. Han S, Roman J. Peroxisome proliferator-activated receptor γ: a novel target for cancer therapeutics? Anti-Cancer Drugs. 2007;18(3):237–244. [PubMed]
35. Giaginis C, Tsantili-Kakoulidou A, Theocharis S. Peroxisome proliferator-activated receptor-γ ligands: potential pharmacological agents for targeting the angiogenesis signaling cascade in cancer. PPAR Research. 2008;2008:12 pages. Article ID 431763. [PMC free article] [PubMed]
36. Roman J. Peroxisome proliferator-activated receptor gamma and lung cancer biology: implications for therapy. Journal of Investigative Medicine. 2008;56(2):528–533. [PubMed]
37. Wang D, DuBois RN. Peroxisome proliferator-activated receptors and progression of colorectal cancer. PPAR Research. 2008;2008:7 pages. Article ID 931074. [PMC free article] [PubMed]
38. Zhou Y-M, Wen Y-H, Kang X-Y, Qian H-H, Yang J-M, Yin Z-F. Troglitazone, a peroxisome proliferator-activated receptor γ ligand, induces growth inhibition and apoptosis of HepG2human liver cancer cells. World Journal of Gastroenterology. 2008;14(14):2168–2173. [PMC free article] [PubMed]
39. Burton JD, Goldenberg DM, Blumenthal RD. Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types. PPAR Research. 2008;2008:7 pages. Article ID 494161. [PMC free article] [PubMed]
40. Bonofiglio D, Gabriele S, Aquila S, et al. Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells. Breast Cancer Research and Treatment. 2009;113(3):423–434. [PubMed]
41. Inamoto T, Shah JB, Kamat AM. Friend or foe? Role of peroxisome proliferator-activated receptor-γ in human bladder cancer. Urologic Oncology. 2009;27(6):585–591. [PubMed]
42. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ Proceedings of the National Academy of Sciences of the United States of America. 1997;94(9):4318–4323. [PubMed]
43. Westendorf T, Graessler J, Kopprasch S. Hypochlorite-oxidized low-density lipoprotein upregulates CD36 and PPARγ mRNA expression and modulates SR-BI gene expression in murine macrophages. Molecular and Cellular Biochemistry. 2005;277(1-2):143–152. [PubMed]
44. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ) Journal of Biological Chemistry. 1995;270(22):12953–12956. [PubMed]
45. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs. Journal of Biological Chemistry. 1997;272(6):3406–3410. [PubMed]
46. Wang Y, Porter WW, Suh N, et al. A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ Molecular Endocrinology. 2000;14(10):1550–1556. [PubMed]
47. Ray DM, Morse KM, Hilchey SP, et al. The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor gamma-independent pathway. Experimental Hematology. 2006;34(9):1202–1211. [PubMed]
48. Ray DM, Akbiyik F, Phipps RP. The peroxisome proliferator-activated receptor γ (PPARγ) ligands 15-deoxy-Δ12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARγ-independent mechanisms. Journal of Immunology. 2006;177(8):5068–5076. [PubMed]
49. Ferguson HE, Kulkarni A, Lehmann GM, et al. Electrophilic peroxisome proliferator-activated receptor-γ ligands have potent antifibrotic effects in human lung fibroblasts. American Journal of Respiratory Cell and Molecular Biology. 2009;41(6):722–730. [PMC free article] [PubMed]
50. Place AE, Suh N, Williams CR, et al. The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clinical Cancer Research. 2003;9(7):2798–2806. [PubMed]
51. Wei S, Yang J, Lee S-L, Kulp SK, Chen C-S. PPARγ-independent antitumor effects of thiazolidinediones. Cancer Letters. 2009;276(2):119–124. [PMC free article] [PubMed]
52. Adams JM, Strasser A. Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Research. 2008;68(11):4018–4021. [PubMed]
53. Allan AL, Vantyghem SA, Tuck AB, Chambers AF. Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Disease. 2006;26(1):87–98. [PubMed]
54. Rak J, Milsom C, Yu J. Vascular determinants of cancer stem cell dormancy—do age and coagulation system play a role? Acta Pathologica, Microbiologica et Immunologica Scandinavica. 2008;116(7-8):660–676. [PubMed]
55. Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Research. 2006;66:4553–4557. [PubMed]
56. Tomasson MH. Cancer stem cells: a guide for skeptics. Journal of Cellular Biochemistry. 2009;106(5):745–749. [PubMed]
57. Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science. 2009;324(5935):1670–1673. [PMC free article] [PubMed]
58. Guzman ML, Jordan CT. Lessons learned from the study of JunB: new insights for normal and leukemia stem cell biology. Cancer Cell. 2009;15(4):252–254. [PubMed]
59. Woodward WA, Bristow RG, Clarke MF, et al. Radiation therapy oncology group translational research program stem cell symposiumml: incorporating stem cell hypotheses into clinical trials. International Journal of Radiation Oncology Biology Physics. 2009;74(5):1580–1591. [PubMed]
60. Woodward WA, Sulman EP. Cancer stem cells: markers or biomarkers? Cancer and Metastasis Reviews. 2008;27(3):459–470. [PubMed]
61. Chearwae W, Bright JJ. PPARγ agonists inhibit growth and expansion of CD133+ brain tumour stem cells. British Journal of Cancer. 2008;99(12):2044–2053. [PMC free article] [PubMed]
62. Saiki M, Hatta Y, Yamazaki T, et al. Pioglitazone inhibits the growth of human leukemia cell lines and primary leukemia cells while sparing normal hematopoietic stem cells. International Journal of Oncology. 2006;29(2):437–443. [PubMed]
63. Jordan CT. The leukemic stem cell. Best Practice and Research in Clinical Haematology. 2007;20(1):13–18. [PMC free article] [PubMed]
64. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nature Reviews Drug Discovery. 2007;6(4):273–286. [PubMed]
65. van Nieuw Amerongen GP, Koolwijk P, Versteilen A, Van Hinsbergh VWM. Involvement of RhoA/Rho kinase signaling in VEGF-induced endothelial cell migration and angiogenesis in vitro. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23(2):211–217. [PubMed]
66. van Hinsbergh VWM, Koolwijk P. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovascular Research. 2008;78(2):203–212. [PubMed]
67. Nagy JA, Senger DR. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype. Experimental Cell Research. 2006;312(5):538–548. [PubMed]
68. Darland DC, D’Amore PA. Blood vessel maturation: vascular development comes of age. Journal of Clinical Investigation. 1999;103(2):157–158. [PMC free article] [PubMed]
69. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. American Journal of Pathology. 1995;146(5):1029–1039. [PubMed]
70. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. Journal of Clinical Investigation. 1999;103(2):159–165. [PMC free article] [PubMed]
71. Hatton JL, Yee LD. Clinical use of PPARγ ligands in cancer. PPAR Research. 2008;2008:13 pages. Article ID 159415. [PMC free article] [PubMed]
72. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. Journal of Cell Science. 2001;114(5):853–865. [PubMed]
73. Gille H, Kowalski J, Li B, et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2): a reassessment using novel receptor-specific vascular endothelial growth factor mutants. Journal of Biological Chemistry. 2001;276(5):3222–3230. [PubMed]
74. Koolwijk P, Peters E, van Der Vecht B, et al. Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (flt-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro. Angiogenesis. 2001;4(1):53–60. [PubMed]
75. Sahni A, Arevalo MT, Sahni SK, Simpson-Haidaris PJ. The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells. International Journal of Cancer. 2009;125(3):577–584. [PubMed]
76. Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO Journal. 1996;15(2):290–298. [PubMed]
77. McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. Journal of Experimental Medicine. 2003;198(6):863–868. [PMC free article] [PubMed]
78. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood. 2007;109(3):1010–1017. [PubMed]
79. Lee S, Chen TT, Barber CL, et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007;130(4):691–703. [PMC free article] [PubMed]
80. Gerber H-P, Malik AK, Solar GP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417(6892):954–958. [PubMed]
81. Lee T-H, Seng S, Sekine M, et al. Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Medicine. 2007;4(6, article e186):1101–1116. [PMC free article] [PubMed]
82. Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS. Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(3):979–984. [PubMed]
83. Masood R, Cai J, Zheng T, Lynne Smith D, Hinton DR, Gill PS. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood. 2001;98(6):1904–1913. [PubMed]
84. Vieira JM, Rosa Santos SC, Espadinha C, et al. Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop. European Journal of Endocrinology. 2005;153(5):701–709. [PubMed]
85. Dias S, Hattori K, Zhu Z, et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. Journal of Clinical Investigation. 2000;106(4):511–521. [PMC free article] [PubMed]
86. Zhang H, Li Y, Li H, et al. Inhibition of both the autocrine and the paracrine growth of human leukemia with a fully human antibody directed against vascular endothelial growth factor receptor 2. Leukemia and Lymphoma. 2004;45(9):1887–1897. [PubMed]
87. Santos SCR, Dias S. Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood. 2004;103(10):3883–3889. [PubMed]
88. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature Reviews Cancer. 2008;8(8):579–591. [PubMed]
89. Mendoza M, Khanna C. Revisiting the seed and soil in cancer metastasis. International Journal of Biochemistry and Cell Biology. 2009;41(7):1452–1462. [PubMed]
90. McGettrick HM, Filer A, Rainger GE, Buckley CD, Nash GB. Modulation of endothelial responses by the stromal microenvironment: effects on leucocyte recruitment. Biochemical Society Transactions. 2007;35(5):1161–1162. [PubMed]
91. Lorusso G, Ruegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochemistry and Cell Biology. 2008;130(6):1091–1103. [PubMed]
92. DeNardo DG, Johansson M, Coussens LM. Immune cells as mediators of solid tumor metastasis. Cancer and Metastasis Reviews. 2008;27(1):11–18. [PubMed]
93. Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annual Review of Pathology. 2006;1:119–150. [PubMed]
94. De Wever O, Demetter P, Mareel M, Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. International Journal of Cancer. 2008;123(10):2229–2238. [PubMed]
95. Lin W-W, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation. 2007;117(5):1175–1183. [PMC free article] [PubMed]
96. Ulisse S, Baldini E, Sorrenti S, D’Armiento M. The urokinase plasminogen activator systemml: a target for anti-cancer therapy. Current Cancer Drug Targets. 2009;9(1):32–71. [PubMed]
97. Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer and Metastasis Reviews. 2006;25(1):9–34. [PubMed]
98. Ribatti D. Endogenous inhibitors of angiogenesis. A historical review. Leukemia Research. 2009;33(5):638–644. [PubMed]
99. Mbeunkui F, Johann DJ., Jr. Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemotherapy and Pharmacology. 2009;63(4):571–582. [PMC free article] [PubMed]
100. Hanna E, Quick J, Libutti SK. The tumour microenvironment: a novel target for cancer therapy. Oral Diseases. 2009;15(1):8–17. [PubMed]
101. Chometon G, Jendrossek V. Targeting the tumour stroma to increase efficacy of chemo- and radiotherapy. Clinical and Translational Oncology. 2009;11(2):75–81. [PubMed]
102. Anton K, Glod J. Targeting the tumor stroma in cancer therapy. Current Pharmaceutical Biotechnology. 2009;10(2):185–191. [PubMed]
103. Bauer AL, Jackson TL, Jiang Y. Topography of extracellular matrix mediates vascular morphogenesis and migration speeds in angiogenesis. PLoS Computational Biology. 2009;5(7, article e1000445) [PMC free article] [PubMed]
104. Baud V, Karin M. Is NF-κB a good target for cancer therapy? Hopes and pitfalls. Nature Reviews Drug Discovery. 2009;8(1):33–40. [PMC free article] [PubMed]
105. Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends in Molecular Medicine. 2008;14(3):109–119. [PubMed]
106. Karin M. The IκB kinase—a bridge between inflammation and cancer. Cell Research. 2008;18(3):334–342. [PubMed]
107. Aboudola S, Kini AR. Angiogenesis in lymphoproliferative disorders: a therapeutic target? Current Opinion in Hematology. 2005;12(4):279–283. [PubMed]
108. Bao Y, Li R, Jiang J, et al. Activation of peroxisome proliferator-activated receptor gamma inhibits endothelin-1-induced cardiac hypertrophy via the calcineurin/NFAT signaling pathway. Molecular and Cellular Biochemistry. 2008;317(1-2):189–196. [PubMed]
109. Spinella F, Garrafa E, Castro VD, et al. Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade. Cancer Research. 2009;69(6):2669–2676. [PubMed]
110. Knowles J, Loizidou M, Taylor I. Endothelin-1 and angiogenesis in cancer. Current Vascular Pharmacology. 2005;3(4):309–314. [PubMed]
111. Grothey A, Ellis LM. Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer Journal. 2008;14(3):170–177. [PubMed]
112. Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clinical Therapeutics. 2006;28(11):1779–1802. [PubMed]
113. Dong X, Han ZC, Yang R. Angiogenesis and antiangiogenic therapy in hematologic malignancies. Critical Reviews in Oncology/Hematology. 2007;62(2):105–118. [PubMed]
114. Li WW, Hutnik M, Gehr G. Antiangiogenesis in haematological malignancies. British Journal of Haematology. 2008;143(5):622–631. [PubMed]
115. Stopeck AT, Unger JM, Rimsza LM, et al. A phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin lymphoma: southwest oncology group study S0108. Leukemia and Lymphoma. 2009;50(5):728–735. [PMC free article] [PubMed]
116. Ribatti D. Lymphangiogenesis in haematological malignancies. Leukemia Research. 2009;33(6):753–755. [PubMed]
117. Ribatti D. Is angiogenesis essential for the progression of hematological malignancies or is it an epiphenomenon? Leukemia. 2009;23(3):433–434. [PubMed]
118. Rajkumar SV, Mesa RA, Tefferi A. A review of angiogenesis and anti-angiogenic therapy in hematologic malignancies. Journal of Hematotherapy and Stem Cell Research. 2002;11(1):33–47. [PubMed]
119. Kessler T, Fehrmann F, Bieker R, Berdel WE, Mesters RM. Vascular endothelial growth factor and its receptor as drug targets in hematological malignancies. Current Drug Targets. 2007;8(2):257–268. [PubMed]
120. Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A. The history of the angiogenic switch concept. Leukemia. 2007;21(1):44–52. [PubMed]
121. O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2):277–285. [PubMed]
122. O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harbor Symposia on Quantitative Biology. 1994;59:471–482. [PubMed]
123. Gupta K, Gupta P, Wild R, Ramakrishnan S, Hebbel RP. Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis. Angiogenesis. 1999;3(2):147–158. [PubMed]
124. Nyberg P, Xie L, Kalluri R. Endogenous inhibitors of angiogenesis. Cancer Research. 2005;65(10):3967–3979. [PubMed]
125. Haviv F, Bradley MF, Kalvin DM, et al. Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. Journal of Medicinal Chemistry. 2005;48(8):2838–2846. [PubMed]
126. Hoekstra R, De Vos FYFL, Eskens FALM, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced cancer. Journal of Clinical Oncology. 2005;23(22):5188–5197. [PubMed]
127. Tomillero A, Moral MA. Gateways to clinical trials. Methods and Findings in Experimental and Clinical Pharmacology. 2008;30(5):383–408. [PubMed]
128. Markovic SN, Suman VJ, Rao RA, et al. A phase II study of ABT-510 (thrombospondin-1 analog) for the treatment of metastatic melanoma. American Journal of Clinical Oncology. 2007;30(3):303–309. [PubMed]
129. Ebbinghaus S, Hussain M, Tannir N, et al. Phase 2 study of ABT-510 in patients with previously untreated advanced renal cell carcinoma. Clinical Cancer Research. 2007;13(22):6689–6695. [PubMed]
130. Brekken RA, Overholser JP, Stastny VA, Waltenberger J, Minna JD, Thorpe PE. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Research. 2000;60(18):5117–5124. [PubMed]
131. Witte L, Hicklin DJ, Zhu Z, et al. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer and Metastasis Reviews. 1998;17(2):155–161. [PubMed]
132. Shinkaruk S, Bayle M, Lain G, Deleris G. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Current Medicinal Chemistry. 2003;3(2):95–117. [PubMed]
133. Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Current Medicinal Chemistry. 2006;13(16):1845–1857. [PubMed]
134. Lien S, Lowman HB. Therapeutic anti-VEGF antibodies. Handbook of Experimental Pharmacology. 2008;(181):131–150. [PubMed]
135. Barakat MR, Kaiser PK. VEGF inhibitors for the treatment of neovascular age-related macular degeneration. Expert Opinion on Investigational Drugs. 2009;18(5):637–646. [PubMed]
136. Ciulla TA, Rosenfeld PJ. Anti-vascular endothelial growth factor therapy for neovascular ocular diseases other than age-related macular degeneration. Current Opinion in Ophthalmology. 2009;20(3):166–174. [PubMed]
137. Quesada AR, Medina MA, Alba E. Playing only one instrument may be not enough: limitations and future of the antiangiogenic treatment of cancer. BioEssays. 2007;29(11):1159–1168. [PubMed]
138. Ellis L, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clinical Cancer Research. 2008;14(20):6371–6375. [PubMed]
139. Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009;15(3):167–170. [PubMed]
140. Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–231. [PMC free article] [PubMed]
141. Ebos JML, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232–239. [PubMed]
142. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Molecular Cancer Therapeutics. 2008;7(12):3670–3684. [PMC free article] [PubMed]
143. Dudley AC, Klagsbrun M. Tumor endothelial cells join the resistance. Clinical Cancer Research. 2009;15(15):4787–4789. [PMC free article] [PubMed]
144. Wei D, Le X, Zheng L, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 2003;22(3):319–329. [PubMed]
145. Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends in Molecular Medicine. 2002;8(4):S62–S67. [PubMed]
146. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1) Molecular Pharmacology. 2006;70(5):1469–1480. [PubMed]
147. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Current Opinion in Cell Biology. 2001;13(2):167–171. [PubMed]
148. Stolze IP, Mole DR, Ratcliffe PJ. Regulation of HIF: prolyl hydroxylases. Novartis Foundation Symposium. 2006;272:15–25. [PubMed]
149. Baumann H, Gauldie J. The acute phase response. Immunology Today. 1994;15(2):74–80. [PubMed]
150. Ohbayashi N, Ikeda O, Taira N, et al. LIF- and IL-6-induced acetylation of STAT3 at Lys-685 through PI3K/Akt activation. Biological and Pharmaceutical Bulletin. 2007;30(10):1860–1864. [PubMed]
151. Xu Q, Briggs J, Park S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005;24(36):5552–5560. [PubMed]
152. Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opinion on Investigational Drugs. 2009;18(1):45–56. [PMC free article] [PubMed]
153. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. European Journal of Cancer. 2005;41(16):2502–2512. [PubMed]
154. Naugler WE, Karin M. NF-κB and cancer—identifying targets and mechanisms. Current Opinion in Genetics and Development. 2008;18(1):19–26. [PMC free article] [PubMed]
155. Keutgens A, Robert I, Viatour P, Chariot A. Deregulated NF-κB activity in haematological malignancies. Biochemical Pharmacology. 2006;72(9):1069–1080. [PubMed]
156. Braun T, Carvalho G, Fabre C, Grosjean J, Fenaux P, Kroemer G. Targeting NF-κB in hematologic malignancies. Cell Death and Differentiation. 2006;13(5):748–758. [PubMed]
157. Aggarwal BB. Nuclear factor-κB: the enemy within. Cancer Cell. 2004;6(3):203–208. [PubMed]
158. Ghisletti S, Huang W, Ogawa S, et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ Molecular Cell. 2007;25(1):57–70. [PMC free article] [PubMed]
159. Yi J-H, Park S-W, Kapadia R, Vemuganti R. Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage. Neurochemistry International. 2007;50(7-8):1014–1027. [PMC free article] [PubMed]
160. Subbaramaiah K, Lin DT, Hart JC, Dannenberg AJ. Peroxisome proliferator-activated receptor γ ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. Journal of Biological Chemistry. 2001;276(15):12440–12448. [PubMed]
161. Kuzu I, Beksac M, Arat M, Celebi H, Elhan AH, Erekul S. Bone marrow microvessel density (MVD) in adult acute myeloid leukemia (AML): therapy induced changes and effects on survival. Leukemia and Lymphoma. 2004;45(6):1185–1190. [PubMed]
162. Anargyrou K, Dimopoulos M-A, Sezer O, Terpos E. Novel anti-myeloma agents and angiogenesis. Leukemia and Lymphoma. 2008;49(4):677–689. [PubMed]
163. Anderson KC. Multiple Myeloma. Advances in disease biology: therapeutic implications. Seminars in Hematology. 2001;38(2, supplement 3):6–10. [PubMed]
164. Anderson KC. Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions. Experimental Hematology. 2007;35(4, supplement 1):155–162. [PubMed]
165. Cibeira MT, Rozman M, Segarra M, et al. Bone marrow angiogenesis and angiogenic factors in multiple myeloma treated with novel agents. Cytokine. 2008;41(3):244–253. [PubMed]
166. Dimopoulos MA, Kastritis E. Thalidomide plus dexamethasone as primary therapy for newly diagnosed patients with multiple myeloma. Nature Clinical Practice Oncology. 2008;5(12):690–691. [PubMed]
167. Folkman J, Rogers MS. Thalidomide for multiple myeloma. The New England Journal of Medicine. 2006;354(22):2389–2390. [PubMed]
168. Vacca A, Scavelli C, Montefusco V, et al. Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. Journal of Clinical Oncology. 2005;23(23):5334–5346. [PubMed]
169. Mangieri D, Nico B, Benagiano V, De Giorgis M, Vacca A, Ribatti D. Angiogenic activity of multiple myeloma endothelial cells in vivo in the chick embryo chorioallantoic membrane assay is associated to a down-regulation in the expression of endogenous endostatin. Journal of Cellular and Molecular Medicine. 2008;12(3):1023–1028. [PubMed]
170. Letilovic T, Vrhovac R, Verstovsek S, Jaksic B, Ferrajoli A. Role of angiogenesis in chronic lymphocytic leukemia. Cancer. 2006;107(5):925–934. [PubMed]
171. Liu P, Li J, Han ZC, et al. Elevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia. Leukemia and Lymphoma. 2005;46(12):1761–1764. [PubMed]
172. Wang ES, Teruya-Feldstein J, Wu Y, Zhu Z, Hicklin DJ, Moore MAS. Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo. Blood. 2004;104(9):2893–2902. [PubMed]
173. Ruan J, Leonard JP. Targeting angiogenesis: a novel, rational therapeutic approach for non-Hodgkin lymphoma. Leukemia and Lymphoma. 2009;50(5):679–681. [PMC free article] [PubMed]
174. Mainou-Fowler T, Angus B, Miller S, Proctor SJ, Taylor PRA, Wood KM. Micro-vessel density and the expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PdEGF) in classical Hodgkin lymphoma (HL) Leukemia and Lymphoma. 2006;47(2):223–230. [PubMed]
175. Rueda A, Olmos D, Villareal V, Torres E, Pajares BI, Alba E. Elevated vascular endothelial growth factor pretreatment levels are correlated with the tumor burden in Hodgkin lymphoma and continue to be elevated in prolonged complete remission. Clinical Lymphoma and Myeloma. 2007;7(6):400–405. [PubMed]
176. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. The New England Journal of Medicine. 2008;359(22):2313–2323. [PubMed]
177. Tzankov A, Heiss S, Ebner S, et al. Angiogenesis in nodal B cell lymphomas: a high throughput study. Journal of Clinical Pathology. 2007;60(5):476–482. [PMC free article] [PubMed]
178. Till KJ, Spiller DG, Harris RJ, Chen H, Zuzel M, Cawley JC. CLL, but not normal, B cells are dependent on autocrine VEGF and α4β1 integrin for chemokine-induced motility on and through endothelium. Blood. 2005;105(12):4813–4819. [PubMed]
179. Matsumoto T, Kobayashi T, Kamata K. Relationships among ET-1, PPARγ, oxidative stress and endothelial dysfunction in diabetic animals. Journal of Smooth Muscle Research. 2008;44(2):41–55. [PubMed]
180. Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109(21, supplement 1):II27–II33. [PubMed]
181. Hafner C, Reichle A, Vogt T. New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARγ agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy. Current Cancer Drug Targets. 2005;5(6):393–419. [PubMed]
182. Michalik L, Wahli W. PPARs mediate lipid signaling in inflammation and cancer. PPAR Research. 2008;2008:15 pages. Article ID 134059. [PMC free article] [PubMed]
183. Gelman L, Fruchart J-C, Auwerx J. An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cellular and Molecular Life Sciences. 1999;55(6-7):932–943. [PubMed]
184. Biscetti F, Straface G, Pitocco D, Zaccardi F, Ghirlanda G, Flex A. Peroxisome proliferator-activated receptors and angiogenesis. Nutrition, Metabolism and Cardiovascular Diseases. 2009;19(11):751–759. [PubMed]
185. Papi A, Rochhi P, Ferreri AM, Guerra F, Orlandi M. Enhanced effects of PPARγ ligands and RXR selective retinoids in combination to inhibit migration and invasiveness in cancer cells. Oncology Reports. 2009;21(4):1083–1089. [PubMed]
186. Yang XY, Wang LH, Farrar WL. A role for PPARγ in the regulation of cytokines in immune cells and cancer. PPAR Research. 2008;2008:12 pages. Article ID 961753. [PMC free article] [PubMed]
187. Tachibana K, Yamasaki D, Ishimoto K, Doi T. The role of PPARs in cancer. PPAR Research. 2008;2008:15 pages. Article ID 102737. [PMC free article] [PubMed]
188. Sainis I, Vareli K, Karavasilis V, Briasoulis E. PPARγ: the portrait of a target ally to cancer chemopreventive agents. PPAR Research. 2008;2008:10 pages. Article ID 436489. [PMC free article] [PubMed]
189. Burstein HJ, Demetri GD, Mueller E, Sarraf P, Spiegelman BM, Winer EP. Use of the peroxisome proliferator-activated receptor (PPAR) γ ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer Research and Treatment. 2003;79(3):391–397. [PubMed]
190. Kulke MH, Demetri GD, Sharpless NE, et al. A phase II study of troglitazone, an activator of the PPARγ receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer Journal. 2002;8(5):395–399. [PubMed]
191. Smith MR, Manola J, Kaufman DS, et al. Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer. 2004;101(7):1569–1574. [PubMed]
192. Gralinski MR, Rowse PE, Breider MA. Effects of troglitazone and pioglitazone on cytokine-mediated endothelial cell proliferation in vitro. Journal of Cardiovascular Pharmacology. 1998;31(6):909–913. [PubMed]
193. Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARγ activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARγ as a potential mediator in vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19(3):546–551. [PubMed]
194. Murata T, He S, Hangai M, et al. Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization. Investigative Ophthalmology and Visual Science. 2000;41(8):2309–2317. [PubMed]
195. Panigrahy D, Singer S, Shen LQ, et al. PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. Journal of Clinical Investigation. 2002;110(7):923–932. [PMC free article] [PubMed]
196. Huang H, Campbell SC, Bedford DF, et al. Peroxisome proliferator-activated receptor γ ligands improve the antitumor efficacy of thrombospondin peptide ABT510. Molecular Cancer Research. 2004;2(10):541–550. [PubMed]
197. Wang C-H, Ciliberti N, Li S-H, et al. Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy. Circulation. 2004;109(11):1392–1400. [PubMed]
198. Sarayba MA, Li L, Tungsiripat T, et al. Inhibition of corneal neovascularization by a peroxisome proliferator-activated receptor-γ ligand. Experimental Eye Research. 2005;80(3):435–442. [PubMed]
199. Peeters LLH, Vigne J-L, Meng KT, Zhao D, Waite LL, Taylor RN. PPARγ represses VEGF expression in human endometrial cells: implications for uterine angiogenesis. Angiogenesis. 2006;8(4):373–379. [PubMed]
200. Pistrosch F, Herbrig K, Oelschlaegel U, et al. PPARγ-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis. 2005;183(1):163–167. [PubMed]
201. Gensch C, Clever YP, Werner C, Hanhoun M, Bohm M, Laufs U. The PPAR-γ agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis. 2007;192(1):67–74. [PubMed]
202. He Q, Pang R, Song X, et al. Rosiglitazone suppresses the growth and invasiveness of SGC-7901 gastric cancer cells and angiogenesis in vitro via PPARγ dependent and independent mechanisms. PPAR Research. 2008;2008:9 pages. Article ID 649808. [PMC free article] [PubMed]
203. Gealekman O, Burkart A, Chouinard M, Nicoloro SM, Straubhaar J, Corvera S. Enhanced angiogenesis in obesity and in response to PPARγ activators through adipocyte VEGF and ANGPTL4 production. American Journal of Physiology. 2008;295(5):E1056–E1064. [PubMed]
204. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN. Current Biology. 2001;11(10):764–768. [PubMed]
205. Dankbar B, Padró T, Leo R, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood. 2000;95(8):2630–2636. [PubMed]
206. Garcia-Bates TM, Peslak SA, Baglole CJ, Maggirwar SB, Bernstein SH, Phipps RP. Peroxisome proliferator-activated receptor gamma overexpression and knockdown: impact on human B cell lymphoma proliferation and survival. Cancer Immunology, Immunotherapy. 2009;58(7):1071–1083. [PMC free article] [PubMed]
207. Garcia-Bates TM, Bernstein SH, Phipps RP. Peroxisome proliferator-activated receptor γ overexpression suppresses growth and induces apoptosis in human multiple myeloma cells. Clinical Cancer Research. 2008;14(20):6414–6425. [PMC free article] [PubMed]
208. Ray DM, Bernstein SH, Phipps RP. Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands. Clinical Immunology. 2004;113(2):203–213. [PubMed]
209. Padilla J, Leung E, Phipps RP. Human B lymphocytes and B lymphomas express PPAR-γ and are killed by PPAR-γ agonists. Clinical Immunology. 2002;103(1):22–33. [PubMed]
210. Padilla J, Kaur K, Cao HJ, Smith TJ, Phipps RP. Peroxisome proliferator activator receptor-γ agonists and 15-deoxy-Δ12,14-PGJ2 induce apoptosis in normal and malignant B-lineage cells. Journal of Immunology. 2000;165(12):6941–6948. [PubMed]
211. Wang LH, Yang XY, Zhang X, et al. Transcriptional inactivation of STAT3 by PPARγ suppresses IL-6-responsive multiple myeloma cells. Immunity. 2004;20(2):205–218. [PubMed]
212. Li HW, Xiao YY, Zhang X, Farrar WL. Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARγ cross talk with NF-κB and C/EBPβ Blood. 2007;110(13):4373–4384. [PubMed]
213. Li HW, Xiao YY, Zhang X, Farrar WL. Nuclear receptors as negative modulators of STAT3 in multiple myeloma. Cell Cycle. 2005;4(2):242–245. [PubMed]
214. Konopleva M, Tsao T, Ruvolo P, et al. Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood. 2002;99(1):326–335. [PubMed]
215. Ling X, Konopleva M, Zeng Z, et al. The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling. Cancer Research. 2007;67(9):4210–4218. [PubMed]
216. Curran MP, McKeage K. Bortezomib: a review of its use in patients with multiple myeloma. Drugs. 2009;69(7):859–888. [PubMed]
217. Roccaro AM, Hideshima T, Raje N, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Research. 2006;66(1):184–191. [PubMed]
218. Hideshima T, Chauhan D, Hayashi T, et al. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene. 2003;22(52):8386–8393. [PubMed]
219. Giralt S, Stadtmauer EA, Harousseau JL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100) Leukemia. 2009;23(10):1904–1912. [PubMed]
220. Chatterjee M, Stühmer T, Herrmann P, Bommert K, Dörken B, Bargou RC. Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells. Blood. 2004;104(12):3712–3721. [PubMed]
221. Epstein RJ. VEGF signaling inhibitors: more pro-apoptotic than anti-angiogenic. Cancer and Metastasis Reviews. 2007;26(3-4):443–452. [PubMed]
222. Anderson CR, Hastings NE, Blackman BR, Price RJ. Capillary sprout endothelial cells exhibit a CD36low phenotype: regulation by shear stress and vascular endothelial growth factor-induced mechanism for attenuating anti-proliferative thrombospondin-1 signaling. American Journal of Pathology. 2008;173(4):1220–1228. [PubMed]
223. Febbraio ML, Guy E, Coburn C, et al. The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36. Molecular and Cellular Biochemistry. 2002;239(1-2):193–197. [PubMed]
224. Sato O, Kuriki C, Fukui Y, Motojima K. Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor α and γ ligands. Journal of Biological Chemistry. 2002;277(18):15703–15711. [PubMed]
225. Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor α and γ activators in a tissue- and inducer-specific manner. Journal of Biological Chemistry. 1998;273(27):16710–16714. [PubMed]
226. Ruiz-Velasco N, Domínguez A, Vega MA. Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-γ ligands putative contribution of Rho GTPases in statin-induced CD36 expression. Biochemical Pharmacology. 2004;67(2):303–313. [PubMed]
227. Simantov R, Silverstein RL. CD36: a critical anti-angiogenic receptor. Frontiers in Bioscience. 2003;8:s874–s882. [PubMed]
228. Swerlick RA, Lee KH, Wick TM, Lawley TJ. Human dermal microvascular endothelial but not human umbilical vein endothelial cells express CD36 in vivo and in vitro. Journal of Immunology. 1992;148(1):78–83. [PubMed]
229. Reiher FK, Volpert OV, Jimenez B, et al. Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics. International Journal of Cancer. 2002;98(5):682–689. [PubMed]
230. Liu J, Lu H, Huang R, et al. Peroxisome proliferator activated receptor-γ ligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemia cells. Cancer Chemotherapy and Pharmacology. 2005;56(4):400–408. [PubMed]
231. Simpson-Haidaris PJ, Rybarczyk B. Tumors and fibrinogen: the role of fibrinogen as an extracellular matrix protein. Annals of the New York Academy of Sciences. 2001;936:406–425. [PubMed]
232. Meltzer PS. Cancer genomics: small RNAs with big impacts. Nature. 2005;435(7043):745–746. [PubMed]
233. Lawrie CH. MicroRNAs and haematology: small molecules, big function. British Journal of Haematology. 2007;137(6):503–512. [PubMed]
234. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–233. [PMC free article] [PubMed]
235. Brennecke J, Stark A, Russell RB, Cohen SM. Principles of microRNA-target recognition. PLoS Biology. 2005;3(3, article e85) [PMC free article] [PubMed]
236. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology. 2009;10(2):126–139. [PubMed]
237. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovascular Research. 2008;79(4):581–588. [PubMed]
238. Mishra PK, Tyagi N, Kumar M, Tyagi SC. MicroRNAs as a therapeutic target for cardiovascular diseases. Journal of Cellular and Molecular Medicine. 2009;13(4):778–789. [PMC free article] [PubMed]
239. Marson A, Levine SS, Cole MF, et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell. 2008;134(3):521–533. [PMC free article] [PubMed]
240. Ruby JG, Jan CH, Bartel DP. Intronic microRNA precursors that bypass Drosha processing. Nature. 2007;448(7149):83–86. [PMC free article] [PubMed]
241. Lee Y, Ahn C, Han J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–419. [PubMed]
242. Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science. 2004;303(5654):95–98. [PubMed]
243. Hutvágner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297(5589):2056–2060. [PubMed]
244. Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Molecular Cell. 2004;15(2):185–197. [PubMed]
245. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Reviews Genetics. 2008;9(2):102–114. [PubMed]
246. Pichiorri F, Suh S-S, Ladetto M, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(35):12885–12890. [PubMed]
247. Fabbri M, Croce C, Calin G. MicroRNAs in the ontogeny of leukemias and lymphomas. Leukemia and Lymphoma. 2009;50(2):160–170. [PubMed]
248. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(24):15524–15529. [PubMed]
249. Roccaro AM, Sacco A, Thompson B, et al. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood. 2009;113(26):6669–6680. [PubMed]
250. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101(11):4569–4575. [PubMed]
251. He L, Thomson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–833. [PubMed]
252. Li Z, Lu J, Sun M, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(40):15535–15540. [PubMed]
253. Li Z, Luo RT, Mi S, et al. Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias. Cancer Research. 2009;69(3):1109–1116. [PMC free article] [PubMed]
254. Hayashita Y, Osada H, Tatematsu Y, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Research. 2005;65(21):9628–9632. [PubMed]
255. Takakura S, Mitsutake N, Nakashima M, et al. Oncogenic role of miR-17-92 cluster in anaplastic thyroid cancer cells. Cancer Science. 2008;99(6):1147–1154. [PubMed]
256. Connolly E, Melegari M, Landgraf P, et al. Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. American Journal of Pathology. 2008;173(3):856–864. [PubMed]
257. Löffler D, Brocke-Heidrich K, Pfeifer G, et al. Interleukin-6-dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood. 2007;110(4):1330–1333. [PubMed]
258. Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Research. 2008;68(19):8164–8172. [PubMed]
259. Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo Y-Y. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Research. 2008;18(3):350–359. [PubMed]
260. Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis: a primer. American Journal of Pathology. 2007;171(3):728–738. [PubMed]
261. Kuehbacher A, Urbich C, Dimmeler S. Targeting microRNA expression to regulate angiogenesis. Trends in Pharmacological Sciences. 2008;29(1):12–15. [PubMed]
262. Asangani IA, Rasheed SAK, Nikolova DA, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128–2136. [PubMed]
263. Baffa R, Fassan M, Volinia S, et al. MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. Journal of Pathology. 2009;219(2):214–221. [PubMed]
264. Yan L-X, Huang X-F, Shao Q, et al. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA. 2008;14(11):2348–2360. [PubMed]
265. Suárez Y, Fernández-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circulation Research. 2007;100(8):1164–1173. [PubMed]
266. Suárez Y, Fernández-Hernando C, Yu J, et al. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(37):14082–14087. [PubMed]
267. Chen Y, Gorski DH. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood. 2008;111(3):1217–1226. [PubMed]
268. Saini HK, Griffiths-Jones S, Enright AJ. Genomic analysis of human microRNA transcripts. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(45):17719–17724. [PubMed]
269. Avnit-Sagi T, Kantorovich L, Kredo-Russo S, Hornstein E, Walker MD. The promoter of the pri-miR-375 gene directs expression selectively to the endocrine pancreas. PLoS ONE. 2009;4(4, article e5033) [PMC free article] [PubMed]
270. Lawrie CH, Cooper CDO, Ballabio E, Chi J, Tramonti D, Hatton CSR. Aberrant expression of microRNA biosynthetic pathway components is a common feature of haematological malignancy. British Journal of Haematology. 2009;145(4):545–548. [PubMed]
271. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139(4):693–706. [PMC free article] [PubMed]
272. Sampson VB, Rong NH, Han J, et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Research. 2007;67(20):9762–9770. [PubMed]
273. Ghosh AK, Shanafelt TD, Cimmino A, et al. Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood. 2009;113(22):5568–5574. [PubMed]
274. Lin Q, Gao Z, Alarcon RM, Ye J, Yun Z. A role of miR-27 in the regulation of adipogenesis. FEBS Journal. 2009;276(8):2348–2358. [PubMed]
275. Morrill AC, Chinn CD. The obesity epidemic in the United States. Journal of Public Health Policy. 2004;25(3-4):353–366. [PubMed]
276. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. The New England Journal of Medicine. 2003;348(17):1625–1638. [PubMed]
277. Larsson SC, Wolk A. Body mass index and risk of multiple myeloma: a meta-analysis. International Journal of Cancer. 2007;121(11):2512–2516. [PubMed]
278. Blair CK, Cerhan JR, Folsom AR, Ross JA. Anthropometric characteristics and risk of multiple myeloma. Epidemiology. 2005;16(5):691–694. [PubMed]
279. Bosetti C, Negri E, Gallus S, Dal Maso L, Franceschi S, La Vecchia C. Anthropometry and multiple myeloma. Epidemiology. 2006;17(3):340–341. [PubMed]
280. Eder K, Baffy N, Falus A, Fulop AK. The major inflammatory mediator interleukin-6 and obesity. Inflammation Research. 2009;58(11):727–736. [PubMed]
281. Karbiener M, Fischer C, Nowitsch S, et al. MicroRNA miR-27b impairs human adipocyte differentiation and targets PPARγ Biochemical and Biophysical Research Communications. 2009;390(2):247–251. [PubMed]
282. Ji J, Zhang J, Huang G, Qian J, Wang X, Mei S. Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation. FEBS Letters. 2009;583(4):759–766. [PubMed]
283. Chintharlapalli S, Papineni S, Abdelrahim M, et al. Oncogenic microRNA-27a is a target for anticancer agent methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate in colon cancer cells. International Journal of Cancer. 2009;125(8):1965–1974. [PMC free article] [PubMed]
284. Lewis BP, Shih I-H, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA target. Cell. 2003;115(7):787–798. [PubMed]
285. John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human microRNA targets. PLoS Biology. 2004;2(11, article e363) [PMC free article] [PubMed]
286. Krek A, Grun D, Poy MN, et al. Combinatorial microRNA target predictions. Nature Genetics. 2005;37(5):495–500. [PubMed]
287. Kim J, Oh Y-S, Shinn S-H. Troglitazone reverses the inhibition of nitric oxide production by high glucose in cultured bovine retinal pericytes. Experimental Eye Research. 2005;81(1):65–70. [PubMed]
288. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29(1):252–260. [PubMed]
289. Ormerod LD, Puklin JE. AIDS-associated intraocular lymphoma causing primary retinal vasculitis. Ocular Immunology and Inflammation. 1997;5(4):271–278. [PubMed]
290. Sagerman RH, Alberti W, Abramson DH. Radiotherapy of Intraocular and Orbital Tumors. New York, NY, USA: Springer; 2003.
291. Chan C-C. Molecular pathology of primary intraocular lymphoma. Transactions of the American Ophthalmological Society. 2003;101:275–292. [PMC free article] [PubMed]
292. Sjö LD. Ophthalmic lymphoma: epidemiology and pathogenesis. Acta Ophthalmologica. 2009;87, thesis1:1–20. [PubMed]
293. Kim SK, Chan C-C, Wallace DJ. Management of primary intraocular lymphoma. Current Oncology Reports. 2005;7(1):74–79. [PubMed]
294. Gordon KB, Rugo HS, Duncan JL, et al. Ocular manifestations of leukemia: leukemic infiltration versus infectious process. Ophthalmology. 2001;108(12):2293–2300. [PubMed]
295. Reddy SC, Jackson N, Menon BS. Ocular involvement in leukemia—a study of 288 cases. Ophthalmologica. 2003;217(6):441–445. [PubMed]
296. Rosenthal AR. Ocular manifestations of leukemia. A review. Ophthalmology. 1983;90(8):899–905. [PubMed]
297. Sharma T, Grewal J, Gupta S, Murray PI. Ophthalmic manifestations of acute leukaemias: the ophthalmologist’s role. Eye. 2004;18(7):663–672. [PubMed]
298. Omoti AE, Omoti CE. Ophthalmic manifestations of multiple myeloma. West African Journal of Medicine. 2007;26(4):265–268. [PubMed]
299. Penn JS, McCollum GW, Barnett JM, Werdich XQ, Koepke KA, Rajaratnam VS. Angiostatic effect of penetrating ocular injury: role of pigment epithelium-derived factor. Investigative Ophthalmology and Visual Science. 2006;47(1):405–414. [PubMed]
300. Aguilar E, Dorrell MI, Friedlander D, et al. Chapter 6. Ocular models of angiogenesis. Methods in Enzymology. 2008;444:115–158. [PubMed]
301. Henkind P. Ocular neovascularization. The Krill memorial lecture. American Journal of Ophthalmology. 1978;85(3):287–301. [PubMed]
302. Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Survey of Ophthalmology. 1998;43(3):245–269. [PubMed]
303. Kim B, Tang Q, Biswas PS, et al. Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes: therapeutic strategy for herpetic stromal keratitis. American Journal of Pathology. 2004;165(6):2177–2185. [PubMed]
304. Zhang SX, Ma JX. Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy. Progress in Retinal and Eye Research. 2007;26(1):1–37. [PubMed]
305. Campochiaro PA. Retinal and choroidal neovascularization. Journal of Cellular Physiology. 2000;184(3):301–310. [PubMed]
306. Pershadsingh HA, Moore DM. PPARγ agonists: potential as therapeutics for neovascular retinopathies. PPAR Research. 2008;2008:13 pages. Article ID 164273. [PMC free article] [PubMed]
307. Tawfik A, Sanders T, Kahook K, Akeel S, Elmarakby A, Al-Shabrawey M. Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Investigative Ophthalmology and Visual Science. 2009;50(2):878–884. [PubMed]
308. Qin S, McLaughlin AP, De Vries GW. Protection of RPE cells from oxidative injury by 15-deoxy-Δ12,14-prostaglandin J2 by augmenting GSH and activating MAPK. Investigative Ophthalmology and Visual Science. 2006;47(11):5098–5105. [PubMed]
309. Willermain F, Dulku S, Gonzalez NS, et al. 15-Deoxy-12,14-prostaglandin J2 inhibits interferon gamma induced MHC class II but not class I expression on ARPE cells through a PPAR gamma independent mechanism. Prostaglandins and Other Lipid Mediators. 2006;80(3-4):136–143. [PubMed]
310. Sassa Y, Hata Y, Aiello LP, Taniguchi Y, Kohno K, Ishibashi T. Bifunctional properties of peroxisome proliferator-activated receptor γ1 in KDR gene regulation mediated via interaction with both Sp1 and Sp3. Diabetes. 2004;53(5):1222–1229. [PubMed]
311. Murata T, Hata Y, Ishibashi T, et al. Response of experimental retinal neovascularization to thiazolidinediones. Archives of Ophthalmology. 2001;119(5):709–717. [PubMed]
312. Aoun P, Simpkins JW, Agarwal N. Role of PPAR-γ ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells. Investigative Ophthalmology and Visual Science. 2003;44(7):2999–3004. [PubMed]
313. Feldon SE, O’Loughlin CW, Ray DM, Landskroner-Eiger S, Seweryniak KE, Phipps RP. Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes. American Journal of Pathology. 2006;169(4):1183–1193. [PubMed]
314. Pasquali D, Pierantoni GM, Fusco A, et al. Fenofibrate increases the expression of high mobility group AT-hook 2 (HMGA2) gene and induces adipocyte differentiation of orbital fibroblasts from Graves’ ophthalmopathy. Journal of Molecular Endocrinology. 2004;33(1):133–143. [PubMed]
315. Cheng H-C, Ho T-C, Chen S-L, Lai H-Y, Hong K-F, Tsao Y-P. Troglitazone suppresses transforming growth factor beta-mediated fibrogenesis in retinal pigment epithelial cells. Molecular Vision. 2008;14:95–104. [PMC free article] [PubMed]
316. Artwohl M, Furnsinn C, Waldhausl W, et al. Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPARγ-independent mechanism. Diabetologia. 2005;48(3):586–594. [PubMed]
317. Shen LQ, Child A, Weber GM, Folkman J, Aiello LP. Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Archives of Ophthalmology. 2008;126(6):793–799. [PubMed]
318. Rumi MAK, Ishihara S, Kazumori H, Kadowaki Y, Kinoshita Y. Can PRARγ ligands be used in cancer therapy? Current Medicinal Chemistry. 2004;4(6):465–477. [PubMed]
319. Papageorgiou E, Pitulis N, Msaouel P, Lembessis P, Koutsilieris M. The non-genomic crosstalk between PPAR-γ ligands and ERK1/2 in cancer cell lines. Expert Opinion on Therapeutic Targets. 2007;11(8):1071–1085. [PubMed]
320. Kelly DP. The pleiotropic nature of the vascular PPAR gene regulatory pathway. Circulation Research. 2001;89(11):935–937. [PubMed]
321. Collins AR. Pleiotropic vascular effects of PPARγ ligands. Drug News and Perspectives. 2003;16(4):197–204. [PubMed]
322. Takano H, Hasegawa H, Zou Y, Komuro I. Pleiotropic actions of PPARγ activators thiazolidinediones in cardiovascular diseases. Current Pharmaceutical Design. 2004;10(22):2779–2786. [PubMed]
323. Julie NL, Julie IM, Kende AI, Wilson GL. Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone. Diabetologia. 2008;51(11):2108–2116. [PubMed]
324. Rizos CV, Elisaf MS, Mikhailidis DP, Liberopoulos EN. How safe is the use of thiazolidinediones in clinical practice? Expert Opinion on Drug Safety. 2009;8(1):15–32. [PubMed]
325. Solomon DH, Cadarette SM, Choudhry NK, Canning C, Levin R, Sturmer T. A cohort study of thiazolidinediones and fractures in older adults with diabetes. Journal of Clinical Endocrinology and Metabolism. 2009;94(8):2792–2798. [PubMed]
326. Kyle RA, Rajkumar SV. Treatment of multiple myeloma: a comprehensive review. Clinical Lymphoma, Myeloma & Leukemia. 2009;9(4):278–288. [PMC free article] [PubMed]
327. Wang M, Tafuri S. Modulation of PPARγ activity with pharmaceutical agents: treatment of insulin resistance and atherosclerosis. Journal of Cellular Biochemistry. 2003;89(1):38–47. [PubMed]
328. Campia U, Matuskey LA, Panza JA. Peroxisome proliferator-activated receptor-γ activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with major cardiovascular risk factors. Circulation. 2006;113(6):867–875. [PubMed]
329. Pfutzner A, Hohberg C, Lubben G, et al. Pioneer study: PPARγ activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Hormone and Metabolic Research. 2005;37(8):510–515. [PubMed]
330. Yamakawa K, Hosoi M, Koyama H, et al. Peroxisome proliferator-activated receptor-γ agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells. Biochemical and Biophysical Research Communications. 2000;271(3):571–574. [PubMed]
331. Chu K, Lee S-T, Koo J-S, et al. Peroxisome proliferator-activated receptor-γ-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia. Brain Research. 2006;1093(1):208–218. [PubMed]
332. Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator-activated receptor-γ-mediated effects in the vasculature. Circulation Research. 2008;102(3):283–294. [PubMed]
333. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Journal of the American Medical Association. 2007;298(10):1189–1195. [PubMed]
334. Zinn A, Felson S, Fisher E, Schwartzbard A. Reassessing the cardiovascular risks and benefits of thiazolidinediones. Clinical Cardiology. 2008;31(9):397–403. [PubMed]
335. Mannucci E, Monami M, Di Bari M, et al. Cardiac safety profile of rosiglitazone. A comprehensive meta-analysis of randomized clinical trials. to appear in International Journal of Cardiology. [PubMed]
336. Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. British Medical Journal. 2009;339, article b2942 [PMC free article] [PubMed]
337. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clinical Cancer Research. 2008;14(1):14–24. [PubMed]
338. Towns K, Bedard PL, Verma S. Matters of the heart: cardiac toxicity of adjuvant systemic therapy for early-stage breast cancer. Current Oncology. 2008;15:S16–S29. [PMC free article] [PubMed]
339. Sereno M, Brunello A, Chiappori A, et al. Cardiac toxicity: old and new issues in anti-cancer drugs. Clinical and Translational Oncology. 2008;10(1):35–46. [PubMed]
340. Gerber DE. Targeted therapies: a new generation of cancer treatments. American Family Physician. 2008;77(3):311–319. [PubMed]
341. Ihle NT, Lemos R, Schwartz D, et al. Peroxisome proliferator-activated receptor γ agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Molecular Cancer Therapeutics. 2009;8(1):94–100. [PMC free article] [PubMed]
342. Veliceasa D, Schulze-Hoepfner FT, Volpert OV. PPARγ and agonists against cancer: rational design of complementation treatments. PPAR Research. 2008;2008:13 pages. Article ID 945275. [PMC free article] [PubMed]
343. Janssen-Heijnen MLG, Maas HAAM, Houterman S, Lemmens VEPP, Rutten HJT, Coebergh JWW. Comorbidity in older surgical cancer patients: influence on patient care and outcome. European Journal of Cancer. 2007;43(15):2179–2193. [PubMed]
344. Shen J, Yang X, Xie B, et al. MicroRNAs regulate ocular neovascularization. Molecular Therapy. 2008;16(7):1208–1216. [PMC free article] [PubMed]
345. Shah YM, Morimura K, Yang Q, Tanabe T, Takagi M, Gonzalez FJ. Peroxisome proliferator-activated receptor α regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Molecular and Cellular Biology. 2007;27(12):4238–4247. [PMC free article] [PubMed]
346. McIntyre RS, Soczynska JK, Woldeyohannes HO, et al. Thiazolidinediones: novel treatments for cognitive deficits in mood disorders? Expert Opinion on Pharmacotherapy. 2007;8(11):1615–1628. [PubMed]
347. Roodhart JM, Langenberg MH, Witteveen E, Voest EE. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Current Clinical Pharmacology. 2008;3(2):132–143. [PubMed]
348. Krone CA, Ely JTA. Controlling hyperglycemia as an adjunct to cancer therapy. Integrative Cancer Therapies. 2005;4(1):25–31. [PubMed]
349. McIntyre TM, Pontsler AV, Silva AR, et al. Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(1):131–136. [PubMed]
350. Schopfer FJ, Lin Y, Baker PRS, et al. Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor γ ligand. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(7):2340–2345. [PubMed]
351. Ulivieri C, Baldari CT. The potential of peroxisome proliferator-activated receptor γ (PPARγ) ligands in the treatment of hematological malignancies. Mini-Reviews in Medicinal Chemistry. 2007;7(9):877–887. [PubMed]
352. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. Journal of Medicinal Chemistry. 2000;43(4):527–550. [PubMed]
353. Wang T, Xu J, Yu X, Yang R, Han ZC. Peroxisome proliferator-activated receptor γ in malignant diseases. Critical Reviews in Oncology/Hematology. 2006;58(1):1–14. [PubMed]
354. Gelman L, Feige JN, Desvergne B. Molecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes. Biochimica et Biophysica Acta. 2007;1771(8):1094–1107. [PubMed]
355. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ Cell. 1995;83(5):803–812. [PubMed]
356. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell. 1995;83(5):813–819. [PubMed]
357. Wigren J, Surapureddi S, Olsson AG, Glass CK, Hammarstrom S, Soderstrom M. Differential recruitment of the coactivator proteins CREB-binding protein and steroid receptor coactivator-1 to peroxisome proliferator-activated receptor gamma/9-cis-retinoic acid receptor heterodimers by ligands present in oxidized low-density lipoprotein. Journal of Endocrinology. 2003;177(2):207–214. [PubMed]
358. Staels B, Fruchart J-C. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005;54(8):2460–2470. [PubMed]
359. Zang C, Liu H, Waechter M, et al. Dual PPARα/γ ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines. Cell Cycle. 2006;5(19):2237–2243. [PubMed]
360. Debril M-B, Renaud J-P, Fajas L, Auwerx J. The pleiotropic functions of peroxisome proliferator-activated receptor γ Journal of Molecular Medicine. 2001;79(1):30–47. [PubMed]
361. Houseknecht KL, Cole BM, Steele PJ. Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: a review. Domestic Animal Endocrinology. 2002;22(1):1–23. [PubMed]
362. Qin C, Morrow D, Stewart J, et al. A new class of peroxisome proliferator-activated receptor γ (PPARγ) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl) methanes. Molecular Cancer Therapeutics. 2004;3(3):247–259. [PubMed]
363. Ito Y, Pandey P, Place A, et al. The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism. Cell Growth and Differentiation. 2000;11(5):261–267. [PubMed]
364. Suh N, Wang Y, Honda T, et al. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9- dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Research. 1999;59(2):336–341. [PubMed]
365. Contractor R, Samudio IJ, Estrov Z, et al. A novel ring-substituted diindolylmethane, 1,1-bis[3′-(5- methoxyindolyl)]-1-(p-t-butylphenyl) methane, inhibits extracellular signal-regulated kinase activation and induces apoptosis in acute myelogenous leukemia. Cancer Research. 2005;65(7):2890–2898. [PubMed]
366. Fujimura S, Suzumiya J, Nakamura K, Ono J. Effects of troglitazone on the growth and differentiation of hematopoietic cell lines. International Journal of Oncology. 1998;13(6):1263–1267. [PubMed]
367. Yamakawa-Karakida N, Sugita K, Inukai T, et al. Ligand activation of peroxisome proliferator-activated receptor γ induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity. Cell Death and Differentiation. 2002;9(5):513–526. [PubMed]
368. Liu JJ, Huang RW, Lin DJ, et al. Expression of survivin and bax/bcl-2 in peroxisome proliferator activated receptor-γ ligands induces apoptosis on human myeloid leukemia cells in vitro. Annals of Oncology. 2005;16(3):455–459. [PubMed]
369. Liu J-J, Liu P-Q, Lin D-J, et al. Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-γ agonists induced apoptosis in human monocyte leukemia cells in vitro. Annals of Hematology. 2007;86(3):173–183. [PubMed]
370. Han H, Shin S-W, Seo C-Y, et al. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ 2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation. Apoptosis. 2007;12(11):2101–2114. [PubMed]
371. Nakata S, Yoshida T, Shiraishi T, et al. 15-Deoxy-Δ12,14-prostaglandin J2 induces death receptor 5 expression through mRNA stabilization independently of PPARγ and potentiates TRAIL-induced apoptosis. Molecular Cancer Therapeutics. 2006;5(7):1827–1835. [PubMed]
372. Sugimura A, Kiriyama Y, Nochi H, et al. Troglitazone suppresses cell growth of myeloid leukemia cell lines by induction of p21WAF1/CIP1 cyclin-dependent kinase inhibitor. Biochemical and Biophysical Research Communications. 1999;261(3):833–837. [PubMed]
373. Konopleva M, Elstner E, McQueen TJ, et al. Peroxisome proliferator-activated receptor and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias. Molecular Cancer Therapeutics. 2004;3(10):1249–1262. [PubMed]
374. Hirase N, Yanase T, Mu Y-M, et al. Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60. Oncology. 1999;57, supplement 2:17–25. [PubMed]
375. Asou H, Verbeek W, Williamson E, et al. Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids. International Journal of Oncology. 1999;15(5):1027–1031. [PubMed]
376. Yasugi E, Horiuchi A, Uemura I, et al. Peroxisome proliferator-activated receptor γ ligands stimulate myeloid differentiation and lipogenensis in human leukemia NB4 cells. Development Growth and Differentiation. 2006;48(3):177–188. [PubMed]
377. Koschmieder S, D’Alo F, Radomska H, et al. CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer-binding protein alpha. Blood. 2007;110(10):3695–3705. [PubMed]
378. Tabe Y, Konopleva M, Kondo Y, et al. PPARγ-active triterpenoid CDDO enhances ATRA-induced differentiation in APL. Cancer Biology and Therapy. 2007;6(12):1967–1977. [PubMed]
379. Konopleva M, Tsao T, Estrov Z, et al. The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Research. 2004;64(21):7927–7935. [PubMed]
380. Ikeda T, Sporn M, Honda T, Gribble GW, Kufe D. The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. Cancer Research. 2003;63(17):5551–5558. [PubMed]
381. Zhu L, Gong B, Bisgaier CL, Aviram M, Newton RS. Induction of PPARγ1 expression in human THP-1 monocytic leukemia cells by 9-cis-retinoic acid is associated with cellular growth suppression. Biochemical and Biophysical Research Communications. 1998;251(3):842–848. [PubMed]
382. Kintscher U, Goetze S, Wakino S, et al. Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes. European Journal of Pharmacology. 2000;401(3):259–270. [PubMed]
383. Liu H, Zang C, Fenner MH, et al. Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARα/γ ligand TZD18. Blood. 2006;107(9):3683–3692. [PubMed]
384. Hirase N, Yanase T, Mu Y-M, et al. Thiazolidinedione suppresses the expression of erythroid phenotype in erythroleukemia cell line K562. Leukemia Research. 2000;24(5):393–400. [PubMed]
385. Zang C, Liu H, Posch MG, et al. Peroxisome proliferator-activated receptor γ ligands induce growth inhibition and apoptosis of human B lymphocytic leukemia. Leukemia Research. 2004;28(4):387–397. [PubMed]
386. Takenokuchi M, Saigo K, Nakamachi Y, et al. Troglitazone inhibits cell growth and induces apoptosis of B-cell acute lymphoblastic leukemia cells with t(14;18) Acta Haematologica. 2006;116(1):30–40. [PubMed]
387. Piva R, Gianferretti P, Ciucci A, Taulli R, Belardo G, Santoro MG. 15-Deoxy-Δ12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-κB activity and down-regulation of antiapoptotic proteins. Blood. 2005;105(4):1750–1758. [PubMed]
388. Harris SG, Phipps RP. Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-γ agonists induce apoptosis in transformed, but not normal, human T lineage cells. Immunology. 2002;105(1):23–34. [PubMed]
389. Yang C, Jo S-H, Csernus B, et al. Activation of peroxisome proliferator-activated receptor γ contributes to the survival of T lymphoma cells by affecting cellular metabolism. American Journal of Pathology. 2007;170(2):722–732. [PubMed]
390. Zhang C, Ni X, Konopleva M, Andreeff M, Duvic M. The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycocis fungoides/Sezary syndrome cells. Journal of Investigative Dermatology. 2004;123(2):380–387. [PubMed]
391. Eucker J, Sterz J, Krebbel H, et al. Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma. Anti-Cancer Drugs. 2006;17(7):763–769. [PubMed]
392. Pedersen IM, Kitada S, Schimmer A, et al. The triterpenoid CDDO induces apoptosis in refractory CLL B cells. Blood. 2002;100(8):2965–2972. [PubMed]
393. Inoue S, Snowden RT, Dyer MJS, Cohen GM. CDDO induces apoptosis via the intrinsic pathway in lymphoid cells. Leukemia. 2004;18(5):948–952. [PubMed]
394. Brookes PS, Morse K, Ray D, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore. Cancer Research. 2007;67(4):1793–1802. [PubMed]
395. Eucker J, Bangeroth K, Zavrski I, et al. Ligands of peroxisome proliferator-activated receptor γ induce apoptosis in multiple myeloma. Anti-Cancer Drugs. 2004;15(10):955–960. [PubMed]
396. Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC. Novel biologically based therapies for Waldenstrom’s macroglobulinemia. Seminars in Oncology. 2003;30(2):309–312. [PubMed]
397. Ikeda T, Nakata Y, Kimura F, et al. Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3, 12-dioxoolean-1,9-dien-28-oic acid. Molecular Cancer Therapeutics. 2004;3(1):39–45. [PubMed]
398. Chauhan D, Li G, Podar K, et al. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood. 2004;103(8):3158–3166. [PubMed]
399. Liby K, Voong N, Williams CR, et al. The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells. Clinical Cancer Research. 2006;12(14, part 1):4288–4293. [PubMed]

Articles from PPAR Research are provided here courtesy of Hindawi Publishing Corporation