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1.  A placenta growth factor 2 variant acts as dominant negative of vascular endothelial growth factor A by heterodimerization mechanism 
Angiogenesis is one of the crucial events for cancer development and growth and vascular endothelial growth factor (VEGF) family plays an essential role in this biological phenomenon. The members of VEGF family mainly involved in angiogenesis are VEGF-A, VEGF-B and placental growth factor (PlGF), which exert their activity through the binding and activation of two VEGF receptors, VEGFR-1 and VEGFR-2. Human VEGF-A and PlGF are expressed in different isoforms and have the peculiarity to form heterodimer if co-expressed in the same cell. The difference of two main human PlGF isoforms, PlGF1 and PlGF2, consist in the exclusive ability of PlGF2 to bind heparin and Neuropilin receptors. As previously reported for PlGF1 isoform, we have generated a PlGF2 variant named PlGF2 -DE, in which the residues D72 and E73 were substituted with alanine, that is unable to bind and activate VEGFR-1 but is still able to heterodimerize with VEGF. Here we report that overexpression in VEGF-A producing human tumor cell line derived from ovarian carcinoma (A2780) of PlGF2-DE variant by stable transfection, significantly reduces the production of VEGF-A homodimer via heterodimerization, determining a strong inhibition of xenograft tumor growth and associated neoangiogenesis, as well as significant reduction of monocyte-macrophage infiltration. Conversely, the overexpression of PlGF2wt, also reducing the VEGF-A homodimer production comparably to PlGF2-DE variant through the generation of VEGF-A/PlGF2 heterodimer, does not inhibit tumor growth and vessel density compared to control, but induces increase of monocyte-macrophage infiltration. Interestingly the comparison of PlGF2wt with PlGF1wt overexpression evidences a significant reduction of monocyte-macrophages recruitment as unique difference among the activity of the two PlGFwt isoforms. Therefore, the ‘less soluble’ PlGF2 shows a limited potential in monocyte-macrophages recruitment. In conclusion data here reported demonstrate that PlGF-DE variant acts as ‘dominant negative’ of VEGF-A independently from the PlGF isoform utilized, that the expression of active PlGF2 homodimer and VEGF-A/PlGF2 heterodimer is sufficient to rescue pro-angiogenic activity lost for reduction of VEGF-A due to heterodimerization mechanism, and that PlGF2 shows lower activity into recruitment of monocyte-macrophage cells compared to PlGF1 isoform.
PMCID: PMC3180054  PMID: 21969185
Angiogenesis; VEGF family; PlGF; VEGF/PlGF heterodimer; ovarian carcinoma; CD31; F4/80
2.  Oncoantigens for an immune prevention of cancer 
Vaccines are one of the main arms of preventive medicine. Recently a large series of experiments with cancer-prone genetically engineered mice have shown that preventive vaccines are also extremely efficacious inhibitors of the progression of carcinogenesis. Early vaccination affords significant and persistent protection, whereas its efficacy fades when neoplastic lesions become more advanced. Our current attempts to use combination strategies and technological advances to make vaccines effective in cancer prevention able to cure more advanced stages of cancer lesions are based on the temporary and systemic Treg removal, the preparation of new bimodular plasmids for DNA vaccination, and the search for fresh target oncoantigens.
PMCID: PMC3180047  PMID: 21969087
Oncoantigens; anti-tumor vaccination; tumor immunoprevention
3.  Molecular aspects of renal cell carcinoma: a review 
Renal cell carcinoma (RCC) is a disease in which cancer cells form in the tubules of the kidney. RCC, the incidence of which is increasing annually, represents five percent of adult epithelial cancers. Clear cell carcinoma represents the most frequent histological subtype. RCC is characterized by a lack of early warning signs, diverse clinical manifestations. Incidentally detected tumors in asymptomatic individuals have been steadily increasing owing to the increased usage of various imaging technologies. Currently there are no recommendations for screening to detect and make an early diagnosis of renal cancer. But in recent years, the discovery of new molecular and cytogenetic markers has led to the recognition and classification of several novel subtypes of RCC, and the introduction of molecular-targeted therapy for advanced-stage RCC. We performed a literature review using PubMed and discuss current knowledge of epidemiology, pathophysiology, evaluation, treatment, and future research directions of RCC.
PMCID: PMC3180049  PMID: 21969126
Renal cell carcinoma; von hippel lindau; chemotherapy
4.  Global expression profiling reveals gain-of-function onco-genic activity of a mutated thyroid hormone receptor in thyroid carcinogenesis 
Thyroid hormone receptors (TRs) are critical in regulating gene expression in normal physiological processes. Decreased expression and/or somatic mutations of TRs have been shown to be associated several types of human cancers including liver, breast, lung, and thyroid. To understand the molecular mechanisms by which mutated TRs promote carcinogenesis, an animal model of follicular thyroid carcinoma (FTC) (Thrbpv/pv mice) was used in the present study. The Thrbpv/pv mouse harbors a knockin dominant negative PV mutation, identified in a patient with resistance to thyroid hormone. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in Thrbpv/pv mice and Thra1-/- Thrb-/- mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5-fold change (p<0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=103: 42.7% of total) with altered gene expression in thyroid tumor cells of Thrbpv/pv mice were associated with tumorigenesis and metastasis; some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in Thrbpv/pv mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRβ evolves with an oncogenic advantage to promote thyroid carcinogenesis.
PMCID: PMC3086765  PMID: 21547001
Mutant TR; thyroid cancer; mouse model; microarray; gene expression
5.  CDH22 expression is reduced in metastatic melanoma 
Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein implicated in cell-cell adhesion and cancer metastasis. The expression of CDH22 has been shown to be increased in colorectal cancers. However, the role of CDH22 in melanomagenesis is not known. To investigate the role of CDH22 in melanoma progression, we examined the expression of CDH22 in melanocytic lesions at different stages and analysed the correlation between CDH22 expression and clinicopathlogic parameters and patient survival. Using tissue microarray and immunohisto-chemistry, we evaluated CDH22 staining in 76 dysplastic nevi, 247 primary melanomas, and 143 metastatic melanomas. We found that metastatic melanomas had a significantly higher percentage of negative CDH22 staining than dysplastic nevi (P = 0.012) and primary melanomas (P = 0.038). CDH22 expression was also reduced in thick (≥2 mm) and ulcerative melanomas (P = 0.003 and 0.022, respectively). Melanomas of AJCC stage II, III, and IV had a higher percentage of negative CDH22 staining than AJCC stage I melanomas (P = 0.004, P < 0.0001, and P = 0.009, respectively). Melanomas with negative CDH22 expression had significantly poorer disease-specific 5-year survival than those with positive CDH22 staining. Additionally, CDH22 expression depended on AJCC stage to predict patient survival. These data indicate that reduced CDH22 expression is associated with melanoma metastasis and poor patient prognosis.
PMCID: PMC3180053  PMID: 21969168
CDH22; melanoma; tissue microarray; immunohistochemistry
6.  Akt signaling is required for glioblastoma maintenance in vivo 
Glioblastoma multiforme (GBM) can be induced in mice through the combined expression of activated forms of KRas and Akt in glial progenitor cells. We have previously demonstrated that KRas is required for the maintenance of these tumors in vivo as inhibition of KRas expression resulted in apoptotic tumor regression and significantly increased survival. To determine the reliance of these tumors on Akt signaling in vivo, we generated a viral vector that allows the expression of Akt to be controlled post-delivery. Survival rates were compared between those animals with continued Akt expression and animals in which expression of Akt was suppressed. Although a fifth of the tumors were refractory to treatment, inhibition of Akt significantly increased the survival of tumor-bearing mice and nearly a fourth of the mice remained in remission four months after the treatment period. These data suggest that Akt is required for glioblastoma maintenance in the context of activated Ras and that loss of Akt expression results in increased survival; therefore, the PI3K/AKT signaling pathway is a viable therapeutic target in this context.
PMCID: PMC3142953  PMID: 21796274
Akt; Ras; glioma; mouse model; tumor maintenance; somatic cell gene delivery; retroviral vector; RCAS; TVA
7.  Therapy of adrenocortical cancer: present and future 
Adrenocortical carcinoma is a rare endocrine malignancy with an estimated worldwide incidence of 0.5 - 2 per million/year. This neoplasm is characterized by a high risk of recurrence and a dismal prognosis owing to unsatisfactory overall survival. Surgery represents the cornerstone of adrenocortical carcinoma therapy, which can be associated to radiotherapy and adjuvant mitotane administration. In advanced cases, different chemotherapy regimens are used, but their relative efficacy is still unknown until the results of clinical trials under way will be published. Novel drugs have been recently developed based on the discovery of molecular pathways that trigger development and evolution of these tumors. More efficient treatments are widely expected in the future from these new targeted therapies as a hope of cure for patients affected with this aggressive malignancy.
PMCID: PMC3180048  PMID: 21969107
Adrenocortical carcinoma; targeted therapy; review; mitotane; radiotherapy; chemotherapy; β-catenin; Steroidogenic factor 1 (SF-1) inverse; mTOR; antagonists
8.  Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer 
Embelin is an active ingredient of traditional herbal medicine that exhibits anti-tumor effects in human prostate cancer cells. However, therapeutic effect of embelin in combination with conventional radiation therapy is not yet determined. In this study, we evaluate the sensitizing potential of embelin on ionizing radiation (IR) in a human prostate cancer model. In vitro, embelin combined with radiation potently suppressed prostate cancer PC-3 cell proliferation that was associated with S and G2/M arrest in cell cycle. Moreover, the combination treatment promoted caspase-independent apoptosis, as evidenced by the increased apoptotic cell death without caspase-3 activation, but not autophagy. Clonogenic survival assay showed that S-phase arrest was required for embelin-mediated radiosensitization. In vivo, embelin significantly improved tumor response to X-ray radiation in the PC-3 xenograft model. Combination therapy produced enhanced tumor growth delay and prolonged time to progression, with minimal systemic toxicity. Immunohistochemistry studies showed that embelin plus IR significantly inhibited cell proliferation, induced apoptosis, and decreased microvessel density in tumors as compared with either treatment alone, suggesting an enhanced combinatory inhibition on tumor suppression and angiogenesis. Our results demonstrate that embelin significantly facilitates tumor suppression by radiation therapy both in vitro and in vivo in the prostate cancer model. This finding warrants embelin as a novel adjuvant therapeutic candidate for the treatment of hormone-refractory prostate cancer that is resistant to radiation therapy.
PMCID: PMC3144474  PMID: 21804946
IAP inhibitor; Embelin; prostate cancer; ionizing radiation therapy
9.  Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression 
We sought to characterize the function of bone marrow stromal cell (BMSC) populations in tumor progression. Because this function may depend on the cell-lineage and mouse strain heterogeneity, we first characterized ex vivo the BMSCs harvested from C57BL/6 versus FVB mice and established their in vivo function in tumor growth and metastasis experiments. All plastic-adherent BMSCs expressed platelet-derived growth factor receptor beta (PDGFRβ) and stem cell antigen 1 (Sca1), consistent with a mesenchymal precursor phenotype, as well as CD80. Moreover, these BMSCs were capable of differentiation along mesenchymal lineage into adipocytes, osteoblasts, chondrocytes or myofibroblasts. However, further phenotypic analysis detected a distinct populations of myeloid (CD11b+) precursor cells amongst the ex vivo expanded BMSCs -with specific surface marker phenotypes and gene expression pattern. When co-implanted with metastatic cancer cells, all the BMSCs persisted and integrated into tumor stroma, but only myeloid BMSCs significantly promoted tumor growth and metastasis. These data demonstrate the differential effect of BMSCs sub-populations on tumor progression. These results may have important implications for anti-tumor therapy and for the use of mesenchymal BMSCs as cell-based therapies.
PMCID: PMC3150110  PMID: 21822499
Myeloid; mesenchymal; bone marrow-derived cells; tumor; metastasis
10.  NF-κB and cancer: a paradigm of Yin-Yang 
Recent studies have clearly linked nuclear factor-kappaB (NF-κB), a transcription factor that plays a central role in regulating immune and inflammatory responses, to tumor development, progression, and metastasis as well as tumor therapy resistance. However, it still remains largely unknown on how the tightly regulated NF-κB becomes constitutively activated in tumorigenesis and how the original cancer immunosurveillance function of NF-κB is transformed to be tumorigenic. To address these important issues for cancer prevention and treatment, we discuss current understanding of the molecular mechanisms and molecules involved in the oncogenic activation of NF-κB. We also discuss current understanding of how NF-κB coordinates the inflammatory and malignant cells in tumorigenesis.
PMCID: PMC3180046  PMID: 21969033
A20; cancer; cancer immunology; cancer immunosurveillance; CYLD; deubiquitination; IκB; IKK; microRNA; NF-κB; oncogene; oncogenesis; PDLIM2; tumor; tumorigenesis; tumor suppressor; ubiquitination; WWOX
11.  Klotho is silenced through promoter hypermethylation in gastric cancer 
As one of major epigenetic changes to inactivate tumor suppressor genes in human carcinogenesis, promoter hypermethylation was proposed as a marker to define novel tumor suppressor genes and predict the prognosis of cancer patients. In the present study, we found KL (klotho) as a novel tumor suppressor gene silenced through promoter hypermethylation in gastric cancer, the second leading cause of cancer death worldwide. KL expression was downregulated in primary gastric carcinoma tissues (n=22, p<0.05) and all of gastric cancer cells lines examined. Ectopic expression of KL inhibited the growth of gastric cancer cells partially through the induction of apoptosis, demonstrating a tumor suppressive role of KL in gastric cancer. Demethylation with 5-aza-2'-deoxycytidine (Aza) increased KL expression and KL promoter was hypermethylated in gastric cancer cell lines as well as some of primary gastric carcinoma tissues (47/99) but none of normal gastric tissues. Importantly, promoter methylation of KL was significantly associated with the poor outcome of gastric cancer patients (p=0.025, Log-rank test), highlighting the relevance of epigenetic inactivation of KL in gastric carcinogenesis. As a summary, we found that KL is a novel tumor suppressor gene epigenetically inactivated in gastric cancer and promoter methylation of KL could be used to predict the prognosis of gastric cancer patients.
PMCID: PMC3180103  PMID: 21969138
KL; gastric cancer; promoter hypermethylation
12.  Decrease in CD8+ lymphocyte number and altered cytokine profile in human prostate cancer 
The tumor microenvironment is comprised of multiple cell types arranged in a three-dimensional structure. Interactions amongst the various cell components play an important role in neoplasia, including the inflammatory reaction that occurs as part of the host response. In this study, the regional lymphocyte subpopulations and cytokine profiles associated with prostate cancer were examined using a quantitative imaging approach and expression microarray analysis. Lymphocytes were measured in four different epithelial phenotypes in prostate cancer specimens: carcinoma; prostatic intraepithelial neoplasia (PIN); benign prostate hyperplasia (BPH); and normal epithelium. The data indicate that CD8 positive, cytotoxic T lymphocytes are significantly decreased in regions adjacent to hyperplasia and carcinoma as compared to normal epithelium and PIN. In contrast the relative number of CD4 positive and CD20 positive lymphocytes did not change markedly. Parallel mRNA expression array analysis of the normal and tumor microenvironments identified a distinct cytokine profile in cancer, with 24 dysregulated genes in tumor epithelium and nine altered in tumor-associated stroma. Overall, these data indicate that the spatial distribution of CD8 positive, cytotoxic T lymphocytes is dysregulated in human prostate glands that contain cancer, and cytokine profiles are altered at the mRNA level.
PMCID: PMC3180108  PMID: 21969236
Prostate cancer; lymphocytes; cytokines; histomathematics; histopathology
14.  Exosome/microvesicle-mediated epigenetic reprogramming of cells 
Microvesicles (MVs) are released by different cell types and may remain in the extracellular space in proximity of the cell of origin or may enter the biological fluids. MVs released by tumor cells are detectable in patients with cancer and their number in the circulation correlates with poor prognosis. Recent studies demonstrated that MVs may act as mediator of cell-to-cell communication thus ensuring short- and long-range exchange of information. Due to their pleyotropic effects, MVs may play a role in the prothrombotic state associated with cancer as well as in cancer development and progression. It has been recently shown that MVs may induce epigenetic changes in target cells by transferring genetic information. This finding suggests that tumor and stromal cells may talk each other via MVs to establish a favorable tumor niche and to promote tumor growth, invasiveness and progression. Moreover, MVs contain genetic material under the form of mRNA and microRNA, that may allow an easy screening for cancer genetic markers and offer new diagnostic and prognostic information. This review presents an overview of the many biological actions of MVs and of the potential role of MV-mediated exchange of genetic information among cells in tumor biology.
PMCID: PMC3180104  PMID: 21969178
Microvesicles; exosomes; angiogenesis; tumor niche; stem cells
15.  Expression profiling and pathway analysis of Krüppel-like factor 4 in mouse embryonic fibroblasts 
Background: Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor with diverse regulatory functions in proliferation, differentiation, and development. KLF4 also plays a role in inflammation, tumorigenesis, and reprogramming of somatic cells to induced pluripotent stem (iPS) cells. To gain insight into the mechanisms by which KLF4 regulates these processes, we conducted DNA microarray analyses to identify differentially expressed genes in mouse embryonic fibroblasts (MEFs) wild type and null for Klf4. Methods: Expression profiles of fibroblasts isolated from mouse embryos wild type or null for the Klf4 alleles were examined by DNA microarrays. Differentially expressed genes were subjected to the Database for Annotation, Visualization and Integrated Discovery (DAVID). The microarray data were also interrogated with the Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA) for pathway identification. Results obtained from the microarray analysis were confirmed by Western blotting for select genes with biological relevance to determine the correlation between mRNA and protein levels. Results: One hundred and sixty three up-regulated and 88 down-regulated genes were identified that demonstrated a fold-change of at least 1.5 and a P-value < 0.05 in Klf4-null MEFs compared to wild type MEFs. Many of the up-regulated genes in Klf4-null MEFs encode proto-oncogenes, growth factors, extracellular matrix, and cell cycle activators. In contrast, genes encoding tumor suppressors and those involved in JAK-STAT signaling pathways are down-regulated in Klf4-null MEFs. IPA and GSEA also identified various pathways that are regulated by KLF4. Lastly, Western blotting of select target genes confirmed the changes revealed by microarray data. Conclusions: These data are not only consistent with previous functional studies of KLF4's role in tumor suppression and somatic cell reprogramming, but also revealed novel target genes that mediate KLF4's functions.
PMCID: PMC3165197  PMID: 21892412
KLF4; microarray; MEF; DAVID; GSEA; IPA; SAM; FDR
16.  E-cadherin plasticity in prostate cancer stem cell invasion 
Prostate cancer that has progressed to metastatic disease remains largely untreatable. Nearly 90% of patients with advanced prostate cancer develop skeletal metastases, resulting in a substantial reduction in the quality of life and a drastic worsening of patient prognosis. The mechanisms involved in prostate cancer cell dissemination, however, remain poorly understood. We previously reported the identification of a highly tumorigenic E-cadherin positive prostate tumor stem cell subpopulation that expressed the embryonic stem cell markers SOX2 and OCT3/4. We herein demonstrate that this subpopulation is also highly invasive and, importantly, is capable of altering its E-cadherin expression during the process of invasion. The non-tumorigenic E-cadherin negative subpopulation which minimally expresses SOX2 or OCT3/4 was found to be poorly invasive. In addition, targeted knockdown of SOX2 or OCT3/4 markedly suppressed the invasion of prostate cancer cells. Taken together, these findings indicate that the expression of SOX2 or OCT3/4 is required for invasive cell capacity, but the ability to modulate E-cadherin is the key permissive factor enabling cancer stem cell invasion in vitro. We therefore propose a model in which the post-epithelial to mesenchymal transition phenotype progresses to a frank, aggressive, and invasive phenotype by a process requiring the acquisition of E-cadherin plasticity. Considering the clinical significance of the metastatic complications of prostate adenocarcinoma, the identification of factors that promote the dissemination of the malignant prostate phenotype is essential to establish effective therapies to combat this disease in future.
PMCID: PMC3180112  PMID: 21968440
Prostate cancer invasion; cancer stem cell; E-cadherin; SOX2; OCT3/4
17.  FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway 
The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to increase as a result of derepression from these protooncogenic kinases. AKT signaling through the FOXO transcription factors appears to be the basis for FHIT gene regulation. Increases in FHIT gene expression are directly dependent on endogenous FOXO3a in MCF7 breast carcinoma cells as evidenced by experiments with RNAi targeting FOXO transcription factor family members. Thus, this is the first report demonstrating that FHIT gene expression is normally repressed in actively cycling cells through the PI3K/AKT/ FOXO3a axis.
PMCID: PMC3130617  PMID: 21743838
FHIT; mitogen signaling; PI3K; AKT; FOXO
18.  Tumor-targeted RNA-interference: functional non-viral nanovectors 
While small interfering RNA (siRNA) and microRNA (miRNA) have attracted extensive attention and showed significant promise for the study, diagnosis and treatment of human cancers, delivering siRNA or miRNA specifically and efficiently into tumor cells in vivo remains a great challenge. Delivery barriers, which arise mainly from the routes of administration associated with complex physiochemical microenvironments of the human body and the unique properties of RNAs, hinder the development of RNA-interference (RNAi)-based therapeutics in clinical practice. However, in available delivery systems, non-viral nanoparticle-based gene/RNA-delivery vectors, or nanovectors, are showing powerful delivery capacities and huge potential for improvements in functional nanomaterials, including novel fabrication approaches which would greatly enhance delivery performance. In this review, we summarize the currently recognized RNAi delivery barriers and the anti-barrier requirements related to vectors' properties. Recent efforts and achievements in the development of novel nanomaterials, nanovectors fabrication methods, and delivery approaches are discussed. We also review the outstanding needs in the areas of material synthesis and assembly, multifunction combinations, proper delivery and assisting approaches that require more intensive investigation for the comprehensive and effective delivery of RNAi by non-viral nanovectors.
PMCID: PMC3092671  PMID: 21572539
Nanoparticles; RNAi; siRNA; miRNA; cancer therapy; tumor-targeting
19.  Genomic profiling of genes contributing to metastasis in a mouse model of thyroid follicular carcinoma 
Metastasis is the major cause of thyroid cancer-related death. However, little is known about the genes involved in the metastatic spread of thyroid carcinomas. We have created a mouse that spontaneously develops metastatic follicular thyroid carcinoma (FTC). This mouse harbors a targeted mutation (denoted TRβPV) in the thyroid hormone receptor β gene (ThrbPV/PV mice). Our recent studies show that the highly elevated level of thyroid stimulating hormone (TSH) in ThrbPV/PV mice promotes proliferation of thyroid tumor cells, but requires the collaboration of the oncogenic action of TRβPV to empower the tumor cells to undergo distant metastasis. To uncover genes destined to drive the metastatic process, we used cDNA microarrays to compare the genomic expression profile of laser capture microdissected thyroid tumor lesions of ThrbPV/PV mice with that of hyperplastic thyroid cells of wild-type mice having elevated TSH induced by treatment with the anti-thyroid drug propylthiouracil (WT-PTU mice). Analyses of microarray data indicated that the expressions of 150 genes were significantly altered between ThrbPV/PV and WT-PTU mice (87 genes had higher expression and 63 genes had lower expression in ThrbPV/PV mice than in WT-PTU mice). Thirty-six percent of genes with altered expression function as key regulators in metastasis. The remaining genes were involved in various cellular processes including metabolism, intracellular trafficking, transcriptional regulation, post-transcriptional modification, and cell-cell/extracellular matrix signaling. The present studies have uncovered novel genes responsible for the metastatic spread of FTC and, furthermore, have shown that the metastatic process of thyroid cancer requires effective collaboration among genes with diverse cellular functions. Importantly, the present studies indicate that the tumor cells in the primary lesions are endowed with the genes destined to promote metastasis. Thus, our study has provided new insights into the understanding of the metastatic spread of human thyroid cancer.
PMCID: PMC3090007  PMID: 21562609
Metastasis; thyroid cancer; mouse model; microarray; gene expression
20.  The immunohistochemical characterization of sarcomatoid malignant mesothelioma of the pleura 
The immunohistochemical characteristics of epithelioid malignant mesothelioma are well described. However, immunohistochemical analyses of sarcomatoid mesothelioma, the less common type, are limited and its distinction from other tumors of the chest wall, lung and pleura is often problematic. We evaluated 24 patients with pleural sarcomatoid mesothelioma who had surgery (12 extrapleural pneumonectomies, 9 pleurectomies and 3 large biopsies) between 1989 and 2005. Clinicopathologic features and demographic data were recorded. We describe immunohistochemical results for 10 antibodies: AE1/AE3, CAM5.2 and MNF-116 keratins, calretinin, WT-1 protein, bcl-2, CD34, desmin, D2-40 and podoplanin. The patients were 23 men and one woman with a median age at diagnosis of 64.7 years (range 47 to 76). Tumor cells were positive for the keratin proteins AE1/AE3 in 18/24 cases, CAM 5.2 in 23/24 cases and MNF-116 in 21/21 cases. Calretinin was positive in 6/24 cases, WT-1 (nuclear) in 8/24 cases, bcl-2 in 0/24 cases, CD34 in 0/24 cases, desmin in 0/24 cases, D2-40 in 24/24 cases and podoplanin in 24/24 cases. This panel of antibodies may be helpful in establishing a pathologic diagnosis of sarcomatoid mesothelioma. In our study, D2-40 and podoplanin are highly sensitive immunohistochemical markers for sarcomatoid mesothelioma. Additional studies are required to define their role in the differential diagnosis of other spindle cell tumors.
PMCID: PMC3180102  PMID: 21969119
Malignant mesothelioma; sarcomatoid; pleura; immunohistochemistry
21.  Harnessing the cell death pathway for targeted cancer treatment 
Genotoxic agents have long targeted apoptotic cell death as a primary means of treating cancer. However, the presence of cellular defects in many cancers has contributed to an acquired resistance to apoptotic cell death, lowering the effectiveness of chemo- and radiotherapies. The mechanisms by which cells achieve this resistance to treatment are still being investigated, but an alternative approach is the study of cell death pathways that are mechanistically distinct from apoptosis. These pathways, including autophagy and necrosis, have arisen as attractive targets for cancer therapy. This review will discuss apoptosis, autophagy, and necrosis in the context of tumorigenesis and drug resistance, as well as provide an up-to-date preclinical and clinical review of inhibitors targeting these cell death pathways for multiple cancer types. The goal of these studies is to identify molecular targets that will enhance the efficacy and specificity of current cancer therapies.
PMCID: PMC3180107  PMID: 21969218
Cancer; apoptosis; autophagy; necrosis; cancer stem cells
22.  Idiopathic bone marrow dysplasia of unknown significance (IDUS): definition, pathogenesis, follow up, and prognosis 
Minimal diagnostic criteria for myelodysplastic syndromes (MDS) include constant cytopenia recorded for at least 6 months, dysplasia, and exclusion of other causes of cytopenia and dysplasia. However, there are patients with dysplastic bone marrow features with or without a karyotype, who have only mild if any cytopenia. This condition has been termed idiopathic dysplasia of unknown significance (IDUS). Out of a series of 1,363 patients with suspected MDS or mild cytopenia seen between 1997 and 2010, we have identified 10 patients with IDUS, and analyzed their clinical course and outcome as well as features potentially involved in disease-evolution. Follow-up ranged between 2 and 13 years. Progression to an overt myeloid neoplasm was observed in 4 patients: two progressed to frank MDS, one to chronic myelomonocytic leukemia, and one to a myelodysplastic/myeloproliferative neoplasm exhibiting 5q-and JAK2 V617F. Consecutive studies revealed that most IDUS patients have an adequate production of erythropoietin (EPO) and sufficient numbers of EPO-responsive erythroid progenitors, features rarely seen in MDS. The erythropoiesis-promoting JAK2 mutation V617F was only detectable in one case. We hypothesize that the dysplastic clone in IDUS cannot manifest as frank MDS because i) the clone retains responsiveness against EPO, and ii) an adequate EPO-production counteracts anemia. Evolution of IDUS to low risk MDS may thus depend on the biological properties of the clone as well as patient-related factors such as EPO production. The latter often decreases with age and may thus explain why MDS often manifests in the elderly.
PMCID: PMC3186051  PMID: 21984971
MDS; diagnostic criteria; IDUS; EPO; BFU-E
23.  Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice 
Mouse models with conditional activation of K-ras (K-rasG12D) are used widely to investigate the role of oncogenic K-ras in a tissue-specific manner. However, the effect of ubiquitous activation of K-ras in adult mice has not been well studied. Herein, we report that systemic activation of K-ras in mice leads to rapid changes in gastric cellular homeostasis. Conditional activation of K-ras results in activation of the MAPK pathway and hyperproliferation of squamous epithelium in the forestomach and metaplasia in the glandular stomach. Parietal cells almost completely disappear from the upper part of the stomach adjacent to forestomach of K-ras activated mice. CDX2, a caudal-related homeobox transcription factor normally expressed in the intestine, is upregulated in parts of the stomach, following activation of K-ras in mice. Cyclooxygenase 2 (COX-2), a mediator of inflammation, is also upregulated in parts of the stomach of the K-ras activated mice with concomitant infiltration of hematopoietic cells in the hyperplastic tissue. Moreover, in K-ras activated mice, the expression of putative progenitor cell marker Dcamkl1 is upregulated in the glandular stomach. Expression of CD44, a candidate stomach cancer stem cell marker, is also increased in forestomach and the glandular stomach. These results suggest that cells of the stomach, potentially stem or progenitor cells, are highly susceptible to K-ras activation-induced initiation of gastric precancerous lesions. The histological changes in the K-ras activated mice resemble the pre-neoplastic changes that take place during gastric carcinogenesis in humans. Thus, a mouse model with systemic K-rasG12D activation could be useful for studying the early molecular events leading to gastric carcinogenesis.
PMCID: PMC3134228  PMID: 21761008
K-ras; intestinal metaplasia; gastric stem cells; Dcamkl1; CD44
24.  Autophagy regulation in cancer development and therapy 
Autophagy is a cellular process to degrade long-lived or malfunctioning proteins and obsolete or damaged organelles. It maintains cellular homeostasis and helps cells survive stressful conditions. Tumor suppressors mostly positively regulate autophagy, whereas oncogene products usually inhibit autophagy. Alterations in key autophagy genes have also been shown to affect cancer development. However, the role of autophagy in cancer depends on the status of the cells and can either suppress or promote tumor growth. In the present review, we report on the current state of knowledge about the reciprocal regulation of autophagy and the potential role of autophagy played in cancer development and therapy.
PMCID: PMC3180058  PMID: 21969237
Autophagy; tumor suppressor; oncogene; cancer; cancer therapy; PTEN; p53; RB; E2F1; Bcl-2
25.  The ups and downs of DNA repair biomarkers for PARP inhibitor therapies 
PARP inhibitors are emerging as a valuable new drug class in the treatment of cancer. Recent discoveries make a compelling case for the complexity of DNA repair biomarker evaluation and underscore the need to examine at multiple biomarkers in a relational manner. This review updates the current trends in DNA repair biomarker strategies in use for the PARP inhibitors and describes the impact of many DNA repair biomarkers on PARP inhibitor benefit in the cancer clinic.
PMCID: PMC3180060  PMID: 21968427
PARP inhibitors; cancer; DNA repair; biomarker

Results 1-25 (26)