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1.  Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis 
In an increasing number of cancers, tumor populations called cancer stem cells (CSCs) or tumor initiating cells have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemo- and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-Catenin and Notch signalling. Novel targeted therapies against the DNA damage checkpoint or stem cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are anti-angiogenic and vascular targeting agents which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of anti-angiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.
doi:10.1200/JCO.2007.15.1829
PMCID: PMC2739000  PMID: 18539962
2.  Adenovirus adenine nucleotide translocator-2 shRNA effectively induces apoptosis and enhances chemosensitivity by the down-regulation of ABCG2 in breast cancer stem-like cells 
Experimental & Molecular Medicine  2011;44(4):251-259.
Cancer stem cells (CSCs) are resistant to chemo- and radio-therapy, and can survive to regenerate new tumors. This is an important reason why various anti-cancer therapies often fail to completely control tumors, although they kill and eliminate the bulk of cancer cells. In this study, we determined whether or not adenine nucleotide translocator-2 (ANT2) suppression could also be effective in inducing cell death of breast cancer stem-like cells. A sub-population (SP; CD44+/CD24-) of breast cancer cells has been reported to have stem/progenitor cell properties. We utilized the adeno-ANT2 shRNA virus to inhibit ANT2 expression and then observed the treatment effect in a SP of breast cancer cell line. In this study, MCF7, MDA-MB-231 cells, and breast epithelial cells (MCF10A) mesenchymally-transdifferentiated through E-cadherin knockdown were used. ANT2 expression was high in both stem-like cells and non-stem-like cells of MCF7 and MDA-MB-231 cells, and was induced and up-regulated by mesenchymal transdifferentiation in MCF10A cells (MCF10AEMT). Knockdown of ANT2 by adeno-shRNA virus efficiently induced apoptotic cell death in the stem-like cells of MCF7 and MDA-MB-231 cells, and MCF10AEMT. Stem-like cells of MCF7 and MDA-MB-231, and MCF10AEMT cells exhibited increased drug (doxorubicin) resistance, and expressed a multi-drug resistant related molecule, ABCG2, at a high level. Adeno-ANT2 shRNA virus markedly sensitized the stem-like cells of MCF7 and MDA-MB-231, and the MCF10AEMT cells to doxorubicin, which was accompanied by down-regulation of ABCG2. Our results suggest that ANT2 suppression by adeno-shRNA virus is an effective strategy to induce cell death and increase the chemosensitivity of stem-like cells in breast cancer.
doi:10.3858/emm.2012.44.4.019
PMCID: PMC3349907  PMID: 22198296
ABCG2 protein, human; adenine nucleotide translocator 2; drug therapy, combination; gene therapy; neoplastic stem cells; RNA, small interfering
3.  Ionizing Radiation Induces Stemness in Cancer Cells 
PLoS ONE  2012;7(8):e43628.
The cancer stem cell (CSC) model posits the presence of a small number of CSCs in the heterogeneous cancer cell population that are ultimately responsible for tumor initiation, as well as cancer recurrence and metastasis. CSCs have been isolated from a variety of human cancers and are able to generate a hierarchical and heterogeneous cancer cell population. CSCs are also resistant to conventional chemo- and radio-therapies. Here we report that ionizing radiation can induce stem cell-like properties in heterogeneous cancer cells. Exposure of non-stem cancer cells to ionizing radiation enhanced spherogenesis, and this was accompanied by upregulation of the pluripotency genes Sox2 and Oct3/4. Knockdown of Sox2 or Oct3/4 inhibited radiation–induced spherogenesis and increased cellular sensitivity to radiation. These data demonstrate that ionizing radiation can activate stemness pathways in heterogeneous cancer cells, resulting in the enrichment of a CSC subpopulation with higher resistance to radiotherapy.
doi:10.1371/journal.pone.0043628
PMCID: PMC3424153  PMID: 22928007
4.  Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis 
Journal of Oncology  2010;2011:941876.
Despite advances in treatment, cancer remains the 2nd most common cause of death in the United States. Poor cure rates may result from the ability of cancer to recur and spread after initial therapies have seemingly eliminated detectable signs of disease. A growing body of evidence supports a role for cancer stem cells (CSCs) in tumor regrowth and spread after initial treatment. Thus, targeting CSCs in combination with traditional induction therapies may improve treatment outcomes and survival rates. Unfortunately, CSCs tend to be resistant to chemo- and radiation therapy, and a better understanding of the mechanisms underlying CSC resistance to treatment is necessary. This paper provides an update on evidence that supports a fundamental role for CSCs in cancer progression, summarizes potential mechanisms of CSC resistance to treatment, and discusses classes of drugs currently in preclinical or clinical testing that show promise at targeting CSCs.
doi:10.1155/2011/941876
PMCID: PMC2958340  PMID: 20981352
5.  Human Pancreatic Cancer Stem Cells: Implications for How We Treat Pancreatic Cancer 
Translational Oncology  2008;1(1):14-18.
Pancreatic cancer has the worst prognosis of any major malignancy, with an annual death rate that approximates the annual incidence rate. Delayed diagnosis, relative chemotherapy and radiation resistance and an intrinsic biologic aggressiveness all contribute to the abysmal prognosis associated with pancreatic cancer. Answers to the frustrating effort to find effective therapies for pancreatic cancer may be gained through a renewed perspective on tumorigenesis as a process governed by a select population of cells, termed cancer stem cells (CSCs). Cancer stem cells, like their normal counterparts, have the properties of self-renewal and multilineage differentiation and possess inherently heightened DNA damage response and repair mechanisms that make them difficult to eradicate. Initially discovered in leukemias, researchers have identified CSCs in several solid-organ malignancies including breast, brain, prostate, and colon cancers. We have recently identified a CSC population in human pancreatic cancers. These pancreatic CSC represent 0.5% to 1.0% of all pancreatic cancer cells and express the cell surface markers CD44, CD24, and epithelial-specific antigen. Pancreatic CSCs have been shown to be resistant to standard chemotherapy and radiation, and devising specific therapies to target this distinct cell population is likely needed to identify effective therapies to treat this dismal disease.
PMCID: PMC2510763  PMID: 18607507
6.  Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells 
Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary agent with pleiotropic effect) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs sub-population. Remnants of spontaneous adenomas from APCMin +/- mice treated with dasatinib and/or curcumin were analyzed for several cancer stem cell markers (ALDH, CD44, CD133 and CD166). Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant (referred to as CR) cells. The effectiveness of the combination therapy in inhibiting growth, invasive potential and stemness was examined in colon cancer CR cells. The residual tumors from APCMin +/- mice treated with dasatinib and/or curcumin showed 80-90% decrease in the expression of the CSC markers ALDH, CD44, CD133, CD166. The colon cancer CR cells showed a higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR HCT-116 and CR HT-29 cells, as determined by Calcusyn analysis. The combinatorial therapy inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. Our data suggest that the combination therapy of dasatinib and curcumin may be a therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.
doi:10.1186/1750-2187-6-7
PMCID: PMC3162943  PMID: 21774804
7.  Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells 
Background
Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy.
Methods
Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44+CD24+ESA+ cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models.
Results
We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44+CD24+ESA+ cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44+CD24-ESA+ cells.
Conclusions
Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors.
doi:10.1186/1479-5876-10-167
PMCID: PMC3478222  PMID: 22901246
Aldehyde dehydrogenase 1; Cancer stem cells; Oncolytic virotherapy; Vaccinia virus; EMT
8.  Cancer stem cells and tumor transdifferentiation: implications for novel therapeutic strategies 
Highly malignant tumors mostly consist of rapidly proliferating cells. However, tumors also contain a few cells in a quiescent state that can be characterized as slow-cycling, expressing markers of stem cells and possessing the ability to initiate new tumors. These quiescent cells, now generally termed ‘cancer stem cells’ (CSC) (or ‘cancer initiating cells’), are capable of regenerating the entire tumor--as it occurs in metastatic spread. This process of tumor initiation by stem-like cells presumably involves differentiation of quiescent CSC into rapidly proliferating tumor cells. An important implication of the presence of slow cycling, quiescent stem-like cells in the tumor and their ability to initiate tumors is that they contribute to the resistance to treatments by conventional chemo- and radiotherapy directed toward killing rapidly dividing cells. However, similar to normal stem cells, the CSC could also potentially transdifferentiate into cell lineages other than the original lineage from which the tumor arose. Therefore, transdifferentiation of CSC offers a possible therapeutic strategy which has not yet been fully exploited. In this article, we provide a comprehensive review of the concepts in tumor cell transdifferentiation and discuss the mechanisms of transdifferentiation with emphasis on their relevance to potential novel treatment strategies.
PMCID: PMC3636725  PMID: 23671816
Cancer stem cells; transdifferentiation; CSC-targeted therapy; tumor Initiating cell; EMT
9.  The Stemness Phenotype Model 
ISRN Oncology  2012;2012:392647.
The identification of a fraction of cancer stem cells (CSCs) associated with resistance to chemotherapy in most solid tumors leads to the dogma that eliminating this fraction will cure cancer. Experimental data has challenged this simplistic and optimistic model. Opposite to the classical cancer stem cell model, we introduced the stemness phenotype model (SPM), which proposed that all glioma cells possess stem cell properties and that the stemness is modulated by the microenvironment. A key prediction of the SPM is that to cure gliomas all gliomas cells (CSCs and non-CSCs) should be eliminated at once. Other theories closely resembling the SPM and its predictions have recently been proposed, suggesting that the SPM may be a useful model for other type of tumors. Here, we review data from other tumors that strongly support the concepts of the SPM applied to gliomas. We include data related to: (1) the presence of a rare but constant fraction of CSCs in established cancer cell lines, (2) the clonal origin of cancer, (3) the symmetrical division, (4) the ability of “non-CSCs” to generate “CSCs,” and (5) the effect of the microenvironment on cancer stemness. The aforenamed issues that decisively supported the SPM proposed for gliomas can also be applied to breast, lung, prostate cancer, and melanoma and perhaps other tumors in general. If the glioma SPM is correct and can be extrapolated to other types of cancer, it will have profound implications in the development of novel modalities for cancer treatment.
doi:10.5402/2012/392647
PMCID: PMC3423925  PMID: 22928120
10.  Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance 
Journal of Oncology  2010;2011:396076.
Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.
doi:10.1155/2011/396076
PMCID: PMC2948913  PMID: 20936110
11.  Cancer Stem Cells: The Final Frontier for Glioma Virotherapy 
Stem cell reviews  2011;7(1):119-129.
Cancer stem cells (CSC) are a very small subset of all cancer cells and possess characteristics very similar to normal stem cells, in particular, the capacity for self-renewal, multipotency and relative quiescence. These chemo- and radiation resistant cells are responsible for maintaining tumor volume leading to therapy failure and recurrence. In glioblastoma multiforme (GBM), the most common primary intracranial malignancy, glioma stem cells have been implicated as one of the key players in treatment failure. Many novel treatment modalities are being investigated to specifically target this small group of cells. In this review, we shed light on one such targeted therapy, specifically, oncolytic virotherapy, and review the literature to highlight the advances and challenges in designing effective oncolytic virotherapy for glioma stem cells.
doi:10.1007/s12015-010-9132-7
PMCID: PMC3026077  PMID: 20237963
Malignant glioma; Glioblastoma multiforme; Stem cells; Oncolytic therapy; Conditionally replicative virus; Adenovirus
12.  Targeting Breast Cancer Stem Cells 
Molecular oncology  2010;4(5):404-419.
The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self renewing cell populations that constitute the bulk of the tumor. Although, the CSC hypothesis does not directly address the cell of origin of cancer, it is postulated that tissue-resident stem or progenitors are the most common targets of transformation. Clinically, CSCs are predicted to mediate tumor recurrence after chemo- and radiation-therapy due to the relative inability of these modalities to effectively target CSCs. If this is the case, then CSC must be efficiently targeted to achieve a true cure. Similarities between normal and malignant stem cells, at the levels of cell-surface proteins, molecular pathways, cell cycle quiescence, and microRNA signaling present challenges in developing CSC-specific therapeutics. Approaches to targeting CSCs include the development of agents targeting known stem cell regulatory pathways as well as unbiased high-throughput siRNA or small-molecule screening. Based on studies of pathways present in normal stem cells, recent work has identified potential “Achilles heals” of CSC, whereas unbiased screening provides opportunities to identify new pathways utilized by CSC as well as develop potential therapeutic agents. Here, we review both approaches and their potential to effectively target breast CSC.
doi:10.1016/j.molonc.2010.06.005
PMCID: PMC3023958  PMID: 20599450
13.  Targeting the osteosarcoma cancer stem cell 
Osteosarcoma is the most common type of solid bone cancer and the second leading cause of cancer-related death in pediatric patients. Many patients are not cured by the current osteosarcoma therapy consisting of combination chemotherapy along with surgery and thus new treatments are urgently needed. In the last decade, cancer stem cells have been identified in many tumors such as leukemia, brain, breast, head and neck, colon, skin, pancreatic, and prostate cancers and these cells are proposed to play major roles in drug resistance, tumor recurrence, and metastasis. Recent studies have shown evidence that osteosarcoma also possesses cancer stem cells. This review summarizes the current knowledge about the osteosarcoma cancer stem cell including the methods used for its isolation, its properties, and its potential as a new target for osteosarcoma treatment.
doi:10.1186/1749-799X-5-78
PMCID: PMC2988747  PMID: 20979639
14.  Cancer stem cells and human malignant melanoma 
Summary
Cancer stem cells (CSC) have been identified in hematological malignancies and several solid cancers. Similar to physiological stem cells, CSC are capable of self-renewal and differentiation and have the potential for indefinite proliferation, a function through which they may cause tumor growth. Although conventional anti-cancer treatments might eradicate most malignant cells in a tumor, they are potentially ineffective against chemoresistant CSC, which may ultimately be responsible for recurrence and progression. Human malignant melanoma is a highly aggressive and drug-resistant cancer. Detection of tumor heterogeneity, undifferentiated molecular signatures, and increased tumorigenicity of melanoma subsets with embryonic-like differentiation plasticity strongly suggest the presence and involvement of malignant melanoma stem cells (MMSC) in the initiation and propagation of this malignancy. Here, we review these findings in the context of functional properties ascribed to melanocyte stem cells and CSC in other cancers. We discuss the association of deregulated signaling pathways, genomic instability, and vasculogenic mimicry phenomena observed in melanoma subpopulations in light of the CSC concept. We propose that a subset of MMSC may be responsible for melanoma therapy-resistance, tumor invasiveness, and neoplastic progression and that targeted abrogation of a MMSC compartment could therefore ultimately lead to stable remissions and perhaps cures of metastatic melanoma.
doi:10.1111/j.1755-148X.2007.00427.x
PMCID: PMC2885609  PMID: 18353142
melanoma; cancer stem cells; tumorigenicity; self-renewal; differentiation; progression; chemoresistance
15.  Sonic Hedgehog Signaling Inhibition Provides Opportunities for Targeted Therapy by Sulforaphane in Regulating Pancreatic Cancer Stem Cell Self-Renewal 
PLoS ONE  2012;7(9):e46083.
Dysregulation of the sonic hedgehog (Shh) signaling pathway has been associated with cancer stem cells (CSC) and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN), an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer.
doi:10.1371/journal.pone.0046083
PMCID: PMC3461003  PMID: 23029396
16.  ALDH Activity Selectively Defines an Enhanced Tumor-Initiating Cell Population Relative to CD133 Expression in Human Pancreatic Adenocarcinoma 
PLoS ONE  2011;6(6):e20636.
Background
Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends.
Methodology/Principal Findings
We have isolated populations of cells with high ALDH activity (ALDHhigh) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDHhigh and ALDHlow cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice.
Conclusions/Significance
We conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133+ and ALDHlow cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDHhigh cell populations. ALDHhigh/CD44+/CD24+ or ALDHlow/CD44+/CD24+ phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy.
doi:10.1371/journal.pone.0020636
PMCID: PMC3113804  PMID: 21695188
17.  Cancer Stem Cells and Therapeutic Targets: An Emerging Field for Cancer Treatment 
Recent paradigm in the field of cancer defines its origin from a small population of fast growing cells known as cancer stem cells (CSCs), and they are mainly responsible for disease aggressiveness, drug resistance and tumor relapse. The existence of CSCs has been proven in different types of cancer and possesses characteristic expression of a wide array of cell surface markers specific to the type of cancer. CSCs have been isolated and enriched using several surface markers in different cancer types. Self-renewal, drug resistance and the ability to transition from epithelial to mesenchymal phenotype are the major features attributed to this fraction of mutated stem cells. The CSC hypothesis proposes that these CSCs mimic stem cells by sharing similar pathways, such as Wnt, SHH, Notch and others. Further, the niche, which in this case is the tumor microenvironment, plays a very important role in the maintenance of CSCs. Altogether, this emerging field of research on CSCs is expected to unveil answers to the most difficult issues of one of the most dreadful diseases called cancer.
doi:10.1007/s13346-012-0095-x
PMCID: PMC3784304  PMID: 24077517
Cancer stem cells; Drug Resistance; CSC markers and Therapy targets
18.  Regulation of Ovarian Cancer Stem Cells or Tumor-Initiating Cells 
Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer.
doi:10.3390/ijms14046624
PMCID: PMC3645658  PMID: 23528891
cancer stem cell or tumor-initiating cells (CSC/TICs); chemoresistance; microRNA; ovarian cancer; recurrence; tumor microenvironment
19.  Natural Compounds' Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells 
PLoS ONE  2014;9(3):e90783.
Background
Accumulating evidence supports the concept that melanoma is highly heterogeneous and sustained by a small subpopulation of melanoma stem-like cells. Those cells are considered as responsible for tumor resistance to therapies. Moreover, melanoma cells are characterized by their high phenotypic plasticity. Consequently, both melanoma stem-like cells and their more differentiated progeny must be eradicated to achieve durable cure. By reevaluating compounds in heterogeneous melanoma populations, it might be possible to select compounds with activity not only against fast-cycling cells but also against cancer stem-like cells. Natural compounds were the focus of the present study.
Methods
We analyzed 120 compounds from The Natural Products Set II to identify compounds active against melanoma populations grown in an anchorage-independent manner and enriched with cells exerting self-renewing capacity. Cell viability, cell cycle arrest, apoptosis, gene expression, clonogenic survival and label-retention were analyzed.
Findings
Several compounds efficiently eradicated cells with clonogenic capacity and nanaomycin A, streptonigrin and toyocamycin were effective at 0.1 µM. Other anti-clonogenic but not highly cytotoxic compounds such as bryostatin 1, siomycin A, illudin M, michellamine B and pentoxifylline markedly reduced the frequency of ABCB5 (ATP-binding cassette, sub-family B, member 5)-positive cells. On the contrary, treatment with maytansine and colchicine selected for cells expressing this transporter. Maytansine, streptonigrin, toyocamycin and colchicine, even if highly cytotoxic, left a small subpopulation of slow-dividing cells unaffected. Compounds selected in the present study differentially altered the expression of melanocyte/melanoma specific microphthalmia-associated transcription factor (MITF) and proto-oncogene c-MYC.
Conclusion
Selected anti-clonogenic compounds might be further investigated as potential adjuvants targeting melanoma stem-like cells in the combined anti-melanoma therapy, whereas selected cytotoxic but not anti-clonogenic compounds, which increased the frequency of ABCB5-positive cells and remained slow-cycling cells unaffected, might be considered as a tool to enrich cultures with cells exhibiting melanoma stem cell characteristics.
doi:10.1371/journal.pone.0090783
PMCID: PMC3940936  PMID: 24595456
20.  Single-cell clones of liver cancer stem cells have the potential of differentiating into different types of tumor cells 
Liu, H | Zhang, W | Jia, Y | Yu, Q | Grau, G E | Peng, L | Ran, Y | Yang, Z | Deng, H | Lou, J
Cell Death & Disease  2013;4(10):e857-.
Cancer stem cells (CSCs) are believed to be a promising target for cancer therapy because these cells are responsible for tumor development, maintenance and chemotherapy resistance. Finding out the critical factors regulating CSC fate is the key for target therapy of CSCs. Just as normal stem cells are regulated by their microenvironment (niche), CSCs are also regulated by cells in the tumor microenvironment. However, whether various tumor microenvironments can induce CSCs to differentiate into different cancer cells is not clear. Here, we show that single-cell-cloned CSCs, accidentally obtained from a human liver cancer microvascular endothelial cells, express classic stem cell markers, genes associated with self-renewal and pluripotent factors and possess colony-forming ability in vitro and the ability of serial transplantation in vivo. The single-cell-cloned CSCs treated with the different tumor cell/tissue-derived conditioned culture medium, which is a mimic of carcinoma microenvironment, could differentiate into corresponding tumor cells and express specific markers of the respective type of tumor cells at the gene, protein and cell levels, respectively. Interestingly, this multilineage differentiation potential of single-cell-cloned liver CSCs sharply declined after the specific knockdown of octamer-binding transcription factor 4 (Oct4) alone, even though they were under the same induction conditions (carcinoma microenvironments). These data support the hypothesis that single-cell-cloned liver CSCs have the potential of differentiating into different types of tumor cells, and the tumor microenvironment does play a crucial role in deciding differentiation directions. Simultaneously, Oct4 in CSCs is indispensable in this process. These factors are promising targets for liver CSC-specific therapy.
doi:10.1038/cddis.2013.340
PMCID: PMC3824650  PMID: 24136221
CSCs; carcinoma/cancer microenvironments; multilineage differentiation potential; Oct4; microvascular endothelial cells
21.  Salinomycin as a Drug for Targeting Human Cancer Stem Cells 
Cancer stem cells (CSCs) represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of malignant cells that comprise a tumor. CSCs possess multiple intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs, and radiation therapy, allowing them to survive standard cancer therapies and to initiate tumor recurrence and metastasis. Various molecular complexes and pathways that confer resistance and survival of CSCs, including expression of ATP-binding cassette (ABC) drug transporters, activation of the Wnt/β-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. Promising results from preclinical trials in human xenograft mice and a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.
doi:10.1155/2012/950658
PMCID: PMC3516046  PMID: 23251084
22.  The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition 
Background
Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs are able to proliferate and self-renew extensively due to their ability to express anti-apoptotic and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate CSCs might have significant clinical implications. The objectives of this study were to examine the molecular mechanisms by which epigallocathechin gallate (EGCG) inhibits stem cell characteristics of prostate CSCs, and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables.
Results
Our data indicate that human prostate cancer cell lines contain a small population of CD44+CD133+ cancer stem cells and their self-renewal capacity is inhibited by EGCG. Furthermore, EGCG inhibits the self-renewal capacity of CD44+α2β1+CD133+ CSCs isolated from human primary prostate tumors, as measured by spheroid formation in suspension. EGCG induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2, survivin and XIAP in CSCs. Furthermore, EGCG inhibits epithelial-mesenchymal transition by inhibiting the expression of vimentin, slug, snail and nuclear β-catenin, and the activity of LEF-1/TCF responsive reporter, and also retards CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Interestingly, quercetin synergizes with EGCG in inhibiting the self-renewal properties of prostate CSCs, inducing apoptosis, and blocking CSC's migration and invasion. These data suggest that EGCG either alone or in combination with quercetin can eliminate cancer stem cell-characteristics.
Conclusion
Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities will be beneficial for prostate cancer prevention and/ortreatment.
doi:10.1186/1750-2187-5-14
PMCID: PMC2933702  PMID: 20718984
23.  A Combination of DR5 Agonistic Monoclonal Antibody with Gemcitabine Targets Pancreatic Cancer Stem Cells and Results in Long-term Disease Control in Human Pancreatic Cancer Model 
Molecular cancer therapeutics  2010;9(9):2582-2592.
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with one of the worst outcomes among all cancers. PDA often recurs after initial treatment to result in patient death despite the use of chemotherapy or radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewal known as cancer stem cells (CSC), which may contribute to therapeutic resistance and metastasis. At present, conventional chemotherapy and radiotherapy are largely ineffective in depleting CSC pool, suggesting the need for novel therapies that specifically target the cancer-sustaining stem cells for tumor eradication and to improve the poor prognosis of PDA patients. In this study, we report that death receptor 5 (DR5) is enriched in pancreatic CSCs compared with the bulk of the tumor cells. Treating a collection of freshly generated patient-derived PDA xenografts with gemcitabine, the first-line chemotherapeutic agent for PDA, is initially effective in reducing tumor size, but largely ineffective in diminishing the CSC populations, and eventually culminated in tumor relapse. However, a combination of tigatuzumab, a fully humanized DR5 agonist monoclonal antibody, with gemcitabine proved to be more efficacious by providing a double hit to kill both CSCs and bulk tumor cells. The combination therapy produced remarkable reduction in pancreatic CSCs, tumor remissions, and significant improvements in time to tumor progression in a model that is considered more difficult to treat. These data provide the rationale to explore the DR5-directed therapies in combination with chemotherapy as a therapeutic option to improve the current standard of care for pancreatic cancer patients.
doi:10.1158/1535-7163.MCT-10-0370
PMCID: PMC3700345  PMID: 20660600
24.  Glioma Stem Cell Research for the development of Immunotherapy 
Glioma, especially high-grade glioblastoma multiforme (GBM), is the most common and aggressive type of brain tumor, accounting for about half of all the primary brain tumors. Despite continued advances in surgery, chemotherapy and radiotherapy, the clinical outcomes remain dismal. The two-year survival rate of GBM is <30%. Better understanding of GBM biology is desirable to develop novel therapies. Recent studies have demonstrated the existence of a small subpopulation of cells with stem like features cancer stem cells otherwise known as (CSC). These GBM CSCs are self-renewable and highly tumorigenic. They are not only chemo-radio- resistant, but also often multi-drug resistance genes and drug transporter genes. These characteristic enable GBM CSCs to survive standard cytotoxic therapies. Among GBM CSCs, CD133+ cells are a well-defined population and are prospectively isolated by their cell-surface marker. There are increasing data that CD133+ CSC presence highly correlates with patient survival. This makes it an ideal immunotherapy target population. In this article, we will review recent studies related with GBM CSCs, particularly CD133+ CSCs as well as the novel therapeutic strategies targeting these cells.
doi:10.1016/j.nec.2009.08.006
PMCID: PMC2786895  PMID: 19944974
cancer stem cell; glioma; CD133+; immunotherapy
25.  The therapeutic promise of the cancer stem cell concept 
Cancer stem cells (CSCs) are a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here, they have been prospectively identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with malignant disease progression in human patients. Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directed therapeutic approaches might represent translationally relevant strategies to improve clinical cancer therapy, in particular for those malignancies that are currently refractory to conventional anticancer agents directed predominantly at tumor bulk populations.
doi:10.1172/JCI41004
PMCID: PMC2798700  PMID: 20051635

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