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1.  The Stem Cell Commons: an exemplar for data integration in the biomedical domain driven by the ISA framework 
Comparisons of stem cell experiments at both molecular and semantic levels remain challenging due to inconsistencies in results, data formats, and descriptions among biomedical research discoveries. The Harvard Stem Cell Institute (HSCI) has created the Stem Cell Commons (stemcellcommons.org), an open, community-based approach to data sharing. Experimental information is integrated using the Investigation-Study-Assay tabular format (ISA-Tab) used by over 30 organizations (ISA Commons, isacommons.org). The early adoption of this format permitted the novel integration of three independent systems to facilitate stem cell data storage, exchange and analysis: the Blood Genomics Repository, the Stem Cell Discovery Engine, and the new Refinery platform that links the Galaxy analytical engine to data repositories.
PMCID: PMC3814497  PMID: 24303302
2.  Cancer stem cells, tumor dormancy, and metastasis 
Tumor cells can persist undetectably for an extended period of time in primary tumors and in disseminated cancer cells. Very little is known about why and how these tumors persist for extended periods of time and then evolve to malignancy. The discovery of cancer stem cells (CSCs) in human tumors challenges our current understanding of tumor recurrence, drug resistance, and metastasis, and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Although overlapping molecules and pathways have been reported to regulate the stem-like phenotype of CSCs and metastasis, accumulated evidence has suggested additional clonal diversity within the stem-like cancer cell subpopulation. This review will describe the current hypothesis linking CSCs and metastasis and summarize mechanisms important for metastatic CSCs to re-initiate tumors in the secondary sites. A better understanding of CSCs’ contribution to clinical tumor dormancy and metastasis will provide new therapeutic revenues to eradicate metastatic tumors and significantly reduce the mortality of cancer patients.
doi:10.3389/fendo.2012.00125
PMCID: PMC3478572  PMID: 23109929
cancer stem cells; metastasis; tumor dormancy; stem-like subpopulations; disseminated CSCs; EMT–MET cooperativity
3.  Understanding and targeting cancer stem cells: therapeutic implications and challenges 
Acta Pharmacologica Sinica  2013;34(6):732-740.
Cancer stem cells (CSCs) have been identified as rare cell populations in many cancers, including leukemia and solid tumors. Accumulating evidence has suggested that CSCs are capable of self-renewal and differentiation into various types of cancer cells. Aberrant regulation of gene expression and some signaling pathways has been observed in CSCs compared to other tumor cells. CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The CSC hypothesis has recently attracted much attention due to the potential for discovery and development of CSC-related therapies and the identification of key molecules involved in controlling the unique properties of CSC populations. Over the past several years, a tremendous amount of effort has been invested in the development of new drugs, such as nanomedicines, that can take advantage of the “Achilles' heel” of CSCs by targeting cell-surface molecular markers or various signaling pathways. Novel compounds and therapeutic strategies that selectively target CSCs have been identified, some of which have been evaluated in preclinical and clinical studies. In this article, we review new findings related to the investigation of the CSC hypothesis, and discuss the crucial pathways involved in regulating the development of CSC populations and the advances in studies of drug resistance. In addition, we review new CSC-targeted therapeutic strategies aiming to eradicate malignancies.
doi:10.1038/aps.2013.27
PMCID: PMC3674516  PMID: 23685952
cancer; stem cell; leukemia; biomarker; ATP-binding cassette transporter; signaling pathway; tumor microenvironment
4.  Shared signaling pathways in normal and breast cancer stem cells 
Recent advances in our understanding of breast cancer biology have led to the identification of a subpopulation of cells within tumors that appear to be responsible for initiating and propagating the cancer. These tumor initiating cells are not only unique in their ability to generate tumors, but also share many similarities with elements of normal adult tissue stem cells, and have therefore been termed cancer stem cells (CSCs). These CSCs often inappropriately use many of the same signaling pathways utilized by their normal stem cell counterparts which may present a challenge to the development of CSC specific therapies. Here, we discuss three major stem cell signaling pathways (Notch, Wnt, and Hedgehog); with a focus on their function in normal mammary gland development and their misuse in breast cancer stem cell fate determination.
doi:10.4103/1477-3163.91413
PMCID: PMC3263309  PMID: 22279423
Cancer stem cell; hedgehog; mammary stem cell; notch; Wnt
5.  Cancer Stem Cells 
Cancer Stem Cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. A number of cell surface markers such as CD44, CD24, and CD133 are often used to identify and enrich CSCs. A regulatory network consisting of microRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways controls the CSC properties. The clinical relevance of CSCs has been strengthened by emerging evidence, demonstrating that CSCs are resistant to conventional chemotherapy and radiation treatment and that CSCs are very likely to be the origin of cancer metastasis. CSCs are believed to be an important target for novel anti-cancer drug discovery. Herein we summarize the current understanding of CSCs, with a focus on the role of miRNA and epithelial mesenchymal transition (EMT), and discuss the clinical application of targeting CSCs for cancer treatment.
doi:10.1016/j.biocel.2012.08.022
PMCID: PMC3496019  PMID: 22981632
Cancer stem cells; tumorigenesis; relapse; metastasis; miRNA
6.  The Notch Pathway Is Important in Maintaining the Cancer Stem Cell Population in Pancreatic Cancer 
PLoS ONE  2014;9(3):e91983.
Background
Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized.
Methods
Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth.
Results
Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population.
Conclusion
The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.
doi:10.1371/journal.pone.0091983
PMCID: PMC3960140  PMID: 24647545
7.  Systems and Network Pharmacology Approaches to Cancer Stem Cells Research and Therapy 
The cancer stem cell (CSC) hypothesis is increasingly being accepted as a model to explain for the functional heterogeneity that is commonly observed in solid tumors. According to this hypothesis, there exists a hierarchical organization of cells within the tumor, in which a differential subpopulation of stem-like cells is responsible for sustaining and recurrence of tumor growth. CSCs have been shown to exist in a variety of solid tumors especially those with known resistant phenotypes such as breast, prostate and pancreatic adenocarcinoma (PDAC). In all these models, the commonality of deregulation of three crucial pathways; Wnt, notch and hedgehog that maintain CSC self-renewal capacity is emerging. Collectively these major pathways and have been linked to the observed resistance of CSC to chemotherapy and radiotherapy. The existing lack of knowledge and our incomplete understanding of the molecular signatures associated with CSCs highlight the need for better approaches in both isolation and identification of unique pathways associated with these cells. In this direction, computational biology, especially systems and network approaches, have proven to be of great utility in unraveling pathway complexities such as those associated with CSCs. With highlights on the most up-to-date molecular, network, cellular, clinical, and therapeutic cancer research findings, this article tends to provide a wealth of insights on systems and network biology approaches to CSC marker identification, the mechanism through which they evade treatment as well as therapeutic approaches that will help in conquering these elusive cells in incurable and refractory malignancies.
doi:10.4172/2157-7633.S7-005
PMCID: PMC3852409  PMID: 24319631
Systems biology; Network pharmacology; Network medicine; Computational biology; Bioinformatics
8.  MicroRNAs in colorectal cancer stem cells: new regulators of cancer stemness? 
Oncogenesis  2012;1(11):e32-.
Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called ‘cancer stem cells' (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding the molecular mechanisms and the possible approaches for colorectal cancer therapy.
doi:10.1038/oncsis.2012.33
PMCID: PMC3511678  PMID: 23552465
microRNAs; CSCs; CRC; stemness
9.  Human Hepatic Cancer Stem Cells are Characterized by Common Stemness Traits and Diverse Oncogenic Pathways 
Hepatology (Baltimore, Md.)  2011;54(3):1031-1042.
Epigenetic mechanisms play critical roles in stem cell biology by maintaining pluripotency of stem cells and promoting differentiation of more mature derivatives. If similar mechanisms are relevant for the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSC isolation and rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell lines were treated with zebularine (ZEB), a potent DNA-methyltransferase1-inhibitor and putative CSCs were isolated by the Side Population (SP) approach. The CSC properties of ZEB-treated and untreated subpopulations were tested by standard in vitro and in vivo assays. Whole transcriptome profiling of isolated CSC was performed to generate CSC signatures. Clinical relevance of the CSC signatures was evaluated in diverse primary human cancers. Epigenetic modulation increased frequency of cells with CSC properties in the SP fraction isolated from human cancer cells as judged by self-renewal, superior tumor-initiating capacity in serial transplantations and direct cell tracking experiments. Integrative transcriptome analysis revealed common traits enriched for stemness-associated genes, although each individual CSC gene expression signature exhibited activation of different oncogenic pathways (e.g. EGFR, SRC and MYC). The common CSC signature was associated with malignant progression, enriched in poorly differentiated tumors and was highly predictive of prognosis in liver and other cancers patients.
CONCLUSION
Epigenetic modulation may provide a tool for prospective isolation and in-depth analysis of CSC. The liver CSC gene signatures are defined by a pernicious interaction of unique oncogene-specific and common stemness traits. These data should facilitate the identifications of therapeutic tools targeting both unique and common features of CSC.
doi:10.1002/hep.24454
PMCID: PMC3179780  PMID: 21618577
Cancer Stem Cells; Liver Cancer; Side-population; Epigenetics
10.  Cancer stem cell, niche and EGFR decide tumor development and treatment response: A bio-computational Simulation Study 
Journal of theoretical biology  2010;269(1):138-149.
Recent research in cancer biology has suggested the hypothesis that tumors are initiated and driven by a small group of cancer stem cells (CSCs). Furthermore, cancer stem cell niches have been found to be essential in determining fates of CSCs, and several signaling pathways have been proven to play a crucial role in cellular behavior, which could be two important factors in cancer development. To better understand the progression, heterogeneity and treatment response of breast cancer, especially in the context of CSCs, we propose a mathematical model based on the cell compartment method. In this model, three compartments of cellular subpopulations are constructed: CSCs, progenitor cells (PCs), and terminal differentiated cells (TCs). Moreover, 1) the cancer stem cell niche is, considered by modeling its effect on division patterns (symmetric or asymmetric) of CSCs, and 2) the EGFR signaling pathway is integrated by modeling its role in cell proliferation, apoptosis. Our simulation results indicate that 1) a higher probability for symmetric division of CSC may result in a faster expansion of tumor population, and for a larger number of niches, the tumor grows at a slower rate, but the final tumor volume is larger; 2) higher EGFR expression correlates to tumors with larger volumes while a saturation function is observed, and 3) treatments that inhibit tyrosine kinase activity of EGFR may not only repress the tumor volume, but also decrease the CSCs percentages by shifting CSCs from symmetric divisions to asymmetric divisions. These findings suggest that therapies should be designed to effectively control or eliminate the symmetric division of CSCs and to reduce or destroy the CSC niches.
doi:10.1016/j.jtbi.2010.10.016
PMCID: PMC3153880  PMID: 20969880
mathematical model; compartment method; signaling pathway; breast cancer; tyrosine kinase inhibitors
11.  Cancer Stem Cells in Breast Cancer 
Cancers  2011;3(1):1311-1328.
The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells in self-renewal, the propagation of differentiated progeny, the expression of specific cell markers and stem cell genes, and the utilization of common signaling pathways and the stem cell niche. However, CSCs differ from normal stem cells in their chemoresistance and their tumorigenic and metastatic activities. In this review, we focus on recent reports regarding the identification of CSC markers and the molecular mechanism of CSC phenotypes to understand the basic properties and molecular target of CSCs. In addition, we especially focus on the CSCs of breast cancer since the use of neoadjuvant chemotherapy can lead to the enrichment of CSCs in patients with that disease. The identification of CSC markers and an improved understanding of the molecular mechanism of CSC phenotypes should lead to progress in cancer therapy and improved prognoses for patients with cancer.
doi:10.3390/cancers3011311
PMCID: PMC3756415  PMID: 24212663
cancer stem cells; breast cancer; EMT; TGF-β; microRNAs
12.  Invasive Prostate Cancer Cells Are Tumor Initiating Cells That Have A Stem Cell-Like Genomic Signature 
Development of metastasis is a leading cause of cancer-induced death. Acquisition of an invasive tumor cell phenotype suggests loss of cell adhesion and basement membrane breakdown during a process termed epithelial-to-mesenchymal transition (EMT). Recently, cancer stem cells (CSC) were discovered to mediate solid tumor initiation and progression. Prostate CSCs are a subpopulation of CD44+ cells within the tumor that give rise to differentiated tumor cells and also self-renew. Using both primary and established prostate cancer cell lines, we tested the assumption that CSCs are more invasive. The ability of unsorted cells and CD44-positve and -negative subpopulations to undergo Matrigel invasion and EMT was evaluated, and the gene expression profiles of these cells were analyzed by microarray and a subset confirmed using QRT-PCR. Our data reveal that a subpopulation of CD44+ CSC-like cells invade Matrigel through EMT, while in contrast, CD44- cells are non-invasive. Furthermore, the genomic profile of the invasive cells closely resembles that of CD44+CD24- prostate CSCs and shows evidence for increased Hedgehog signaling. Finally, invasive cells from DU145 and primary prostate cancer cells are more tumorigenic in NOD/SCID mice compared with non-invasive cells. Our data strongly suggest that basement membrane invasion, an early and necessary step in metastasis development, is mediated by these potential cancer stem cells.
doi:10.1007/s10585-009-9242-2
PMCID: PMC2782741  PMID: 19221883
cancer stem cells; metastasis; invasion; EMT; prostate cancer; hedgehog
13.  De-Regulated MicroRNAs in Pediatric Cancer Stem Cells Target Pathways Involved in Cell Proliferation, Cell Cycle and Development 
PLoS ONE  2013;8(4):e61622.
Background
microRNAs (miRNAs) have been implicated in the control of many biological processes and their deregulation has been associated with many cancers. In recent years, the cancer stem cell (CSC) concept has been applied to many cancers including pediatric. We hypothesized that a common signature of deregulated miRNAs in the CSCs fraction may explain the disrupted signaling pathways in CSCs.
Methodology/Results
Using a high throughput qPCR approach we identified 26 CSC associated differentially expressed miRNAs (DEmiRs). Using BCmicrO algorithm 865 potential CSC associated DEmiR targets were obtained. These potential targets were subjected to KEGG, Biocarta and Gene Ontology pathway and biological processes analysis. Four annotated pathways were enriched: cell cycle, cell proliferation, p53 and TGF-beta/BMP. Knocking down hsa-miR-21-5p, hsa-miR-181c-5p and hsa-miR-135b-5p using antisense oligonucleotides and small interfering RNA in cell lines led to the depletion of the CSC fraction and impairment of sphere formation (CSC surrogate assays).
Conclusion
Our findings indicated that CSC associated DEmiRs and the putative pathways they regulate may have potential therapeutic applications in pediatric cancers.
doi:10.1371/journal.pone.0061622
PMCID: PMC3629228  PMID: 23613887
14.  Radiation Responses of Cancer Stem Cells 
Journal of cellular biochemistry  2009;108(2):339-342.
Recent experimental evidence indicates that many solid cancers have a hierarchical organization structure with a subpopulation of cancer stem cells (CSCs). The ability to identify CSCs prospectively now allows for testing the responses of CSCs to treatment modalities like radiation therapy. Initial studies have found CSCs in glioma and breast cancer relatively resistant to ionizing radiation and possible mechanisms behind this resistance have been explored. This review summarizes the landmark publications in this young field with an emphasis on the radiation responses of CSCs. The existence of CSCs in solid cancers place restrictions on the interpretation of many radiobiological observations, while explaining others. The fact that these cells may be a relatively quiescent subpopulation that are metabolically distinct from the other cells in the tumor has implications for both imaging and therapy of cancer. This is particularly true for biological targeting of cancer for enhanced radiotherapeutic benefit, which must consider whether the unique properties of this subpopulation allow it to avoid such therapies.
doi:10.1002/jcb.22275
PMCID: PMC2865474  PMID: 19623582
cancer stem cells; cancer initiating cells; radiation biology
15.  New insights into prostate cancer stem cells 
Cell Cycle  2013;12(4):579-586.
Prostate cancer (PCa) remains one of the most prevalent malignancies affecting men in the western world. The etiology for PCa development and molecular mechanisms underlying castration-resistant progression are incompletely understood. Emerging evidence from many tumor systems has shown the existence of distinct subpopulations of stem like-cancer cells termed cancer stem cells (CSCs), which may be involved in tumor initiation, progression, metastasis and therapy resistance. Prostate cancer stem cells (PCSCs) have also been identified using different experimental strategies in distinct model systems. In this brief review, we summarize our current knowledge of normal prostate stem/progenitor cells, highlight recent progress on PCSCs, expound on the potential cell-of-origin for PCa and discuss the involvement of PCSCs in PCa progression and castration resistance. Elucidation of the phenotypic and functional properties and molecular regulation of PCSCs will help us better understand PCa biology and may lead to development of novel therapeutics targeting castration-resistant PCa cells.
doi:10.4161/cc.23721
PMCID: PMC3594258  PMID: 23370446
prostate cancer; cancer stem cells; prostate cancer stem cells; differentiation; therapy resistance
16.  Cancer stem cells in bladder cancer: a revisited and evolving concept 
Current opinion in urology  2010;20(5):393-397.
Purpose of review
Recently, the prospective isolation and characterization of cancer stem cells (CSCs) from various human malignancies revealed that they are resistant to radiation and chemotherapies. Therefore, CSCs may be the “roots” and ideal target for therapeutic intervention. Here, we will focus on reviewing the historical perspective, recent literatures on bladder cancer stem cells and their clinical implications.
Recent findings
Cancer stem cells have been prospectively isolated from bladder cancer tissues from patient specimens, established cancer cell lines and xenografts, based on the expression of a combination of cell surface receptors, cytokeratin markers, drug transporters and the efficient efflux of the Hoechst 33342 dye (side population). Further, global gene expression profiling of CSCs revealed an activated gene-signature of CSCs similar to that of aggressive bladder cancer, supporting the concept that a tumor cell subpopulation is contributing to bladder cancer progression. Finally, our studies on the preclinical targeting of bladder CSCs in vitro and in xenografts using a blocking antibody for CD47 reveal promising efficacy.
Summary
Functionally distinct CSCs exist in human bladder cancer and can be prospectively isolated. Continuing research will be important to identify their cell of origin, programs balancing self-renewal and differentiation, and to identify additional therapeutic options to target bladder CSCs.
doi:10.1097/MOU.0b013e32833cc9df
PMCID: PMC2997612  PMID: 20657288
Bladder cancer; cancer stem cells; basal cells; therapeutic targeting; CD47
17.  Genomic profiling of tumor initiating prostatospheres 
BMC Genomics  2010;11:324.
Background
The cancer stem cell (CSC) hypothesis proposes that a population of tumor cells bearing stem cell properties is responsible for the origin and maintenance of tumors. Normal and cancer stem cells possess the ability to grow in vitro as self-renewing spheres, but the molecular basis of this phenotype remains largely unknown. We intended to establish a comprehensive culture system to grow prostatospheres (PSs) from both cancer cell lines and patient tumors. We then used gene expression microarrays to gain insight on the molecular pathways that sustain the PS tumor initiating cell (TIC) phenotype.
Results
Traditional stem cell medium (SCM) supplemented with Knockout™SR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.
Conclusions
We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.
doi:10.1186/1471-2164-11-324
PMCID: PMC2900264  PMID: 20500816
18.  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
19.  Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation 
PLoS ONE  2007;2(3):e293.
Cancer stem cells (CSCs) have been identified in hematopoietic and solid tumors. However, their precursors—namely, precancerous stem cells (pCSCs) —have not been characterized. Here we experimentally define the pCSCs that have the potential for both benign and malignant differentiation, depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer, they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice. The progress of the pCSCs to cancers is associated with the up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, the pCSCs are regulated by the PIWI/AGO family gene called piwil2. Our results provide clear evidence that a single clone of pCSCs has the potential for both benign and malignant differentiation, depending on the environmental cues. We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers.
doi:10.1371/journal.pone.0000293
PMCID: PMC1808425  PMID: 17356702
20.  Colorectal Cancer Stem Cells: Biology and Therapeutic Implications 
The hypothesis that cancer is driven by a subpopulation of tumor-initiating or cancer stem cells (CSC), defined by their selective ability for extensive self-renewal and capacity to give rise to nontumorigenic cancer cell progeny through differentiation, has been validated experimentally in diverse human malignancies. Translational relevance of the CSC hypothesis is underlined by emerging novel strategies designed to target all subpopulations within a given tumor in order to effect cancer eradication and improve patient outcomes. Colorectal cancer stem cells (CRSCs) have been identified and successfully isolated by several research groups based on distinct cell-surface marker characteristics. Identification of CRSC populations has led to a wave of discoveries describing novel self-renewal and drug resistance mechanisms in colorectal cancer that represent novel future therapeutic targets. In this review, we will discuss emerging CRSC-specific pathways and the therapeutic promise of targeting this cancer population in colorectal cancer patients.
doi:10.1007/s11888-011-0093-2
PMCID: PMC3087297  PMID: 21552371
Colorectal cancer; Stem cells; CD133; CD44; ALDH1; ESA; CD166; Therapy; Chemoresistance; Radioresistance; Targeting; ABCB5; 5-FU; Oxaliplatin; Wnt; APC; Lgr5; SMAD4; BMP4; Notch; Il-4; Aurora-A kinase
21.  The epigenome of AML stem and progenitor cells 
Epigenetics  2013;8(1):92-104.
Acute myeloid leukemia (AML) is sustained by a population of cancer stem cells (CSCs or cancer-initiating cell). The mechanisms underlying switches from CSCs to non-CSCs in vivo remain to be understood. We address this issue in AML from the aspect of epigenetics using genome-wide screening for DNA methylation and selected histone modifications. We found no major differences in DNA methylation, especially in promoter CpG islands, between CSCs and non-CSCs. By contrast, we found thousands of genes that change H3K4me3 and/or H3K27me3 status between stem and progenitor cells as well as between progenitor and mature cells. Stem cell related pathways and proliferation or metabolism related pathways characterize genes differentially enriched for H3K4me3/H3K27me3 in stem and progenitor populations. Bivalent genes in stem cells are more plastic during differentiation and are more likely to lose H3K4me3 than to lose H3K27me3, consistent with increasingly closed chromatin state with differentiation. Our data indicates that histone modifications but not promoter DNA methylation are involved in switches from CSCs to non-CSCs in AML.
doi:10.4161/epi.23243
PMCID: PMC3549884  PMID: 23249680
DNA methylation; histone modification; AML; stem; progenitor
22.  TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells* 
Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes-1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.
doi:10.1016/j.bbrc.2012.06.065
PMCID: PMC3488595  PMID: 22728043
TNFα; OSCC; cancer stem cells; Notch; Hes1
23.  Identification of Vitronectin as an Extrinsic Inducer of Cancer Stem Cell Differentiation and Tumor Formation 
Stem cells (Dayton, Ohio)  2010;28(3):390-398.
There is mounting evidence that tumors are initiated by a rare subset of cells called cancer stem cells (CSCs). CSCs are generally quiescent, self-renew, form tumors at low numbers, and give rise to the heterogeneous cell types found within a tumor. CSCs isolated from multiple tumor types differentiate both in vivo and in vitro when cultured in serum, yet the factors responsible for their differentiation have not yet been identified. Here we show that vitronectin is the component of human serum driving stem cell differentiation through an integrin αVβ3-dependent mechanism. CSCs cultured on vitronectin result in downregulation of stem cell genes, modulation of differentiation markers, and loss of β-catenin nuclear localization. Blocking integrin αVβ3 inhibits differentiation and subsequently tumor formation. Thus, CSCs must be engaged by one or more extracellular signals to differentiate and initiate tumor formation, defining a new axis for future novel therapies aimed at both the extrinsic and intracellular pathways.
doi:10.1002/stem.271
PMCID: PMC3448441  PMID: 19998373
Prostate cancer; Breast cancer; Tumor-initiating; Vitronectin; Arginine-glycine-aspartic acid peptide; Integrin alphaVbeta3
24.  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
25.  CCL2 mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells 
Cancer Research  2012;72(11):2768-2779.
Cancer stem cells (CSCs) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer (BC) stem cells. We found that compared to normal fibroblasts, primary cancer-associated fibroblasts (CAFs) and fibroblasts activated by co-cultured BC cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in BC cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse BC-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in BC cells, constituting a “cancer-stroma-cancer” signaling circuit. In a xenograft model of paired fibroblasts and BC tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary BCs, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.
doi:10.1158/0008-5472.CAN-11-3567
PMCID: PMC3367125  PMID: 22472119
breast cancer; cancer stem cells; chemokine (C-C motif) ligand 2; tumor microenvironment; stromal fibroblasts

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