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• W2058172383 abstract "Cancer stem cells (CSCs) are defined by their ability to (i) fully recapitulate the tumor of origin when transplanted into immunodeficient mouse hosts, and (ii) self-renew, demonstrated by their ability to be serially transplanted. These properties suggest that CSCs are required for tumor maintenance and metastasis; thus, it has been predicted that CSC elimination is required for cure. This prediction has profoundly altered paradigms for cancer research, compelling investigators to prospectively isolate CSCs to characterize the molecular pathways regulating their behavior. Many potential strategies for CSC-directed therapy have been proposed, but few studies have rigorously demonstrated their efficacy using in vivo models. Herein, we highlight recent studies that demonstrate the utility of CSC-directed therapies and discuss the implications of the CSC hypothesis to experimental design and therapeutic strategies. Cancer stem cells (CSCs) are defined by their ability to (i) fully recapitulate the tumor of origin when transplanted into immunodeficient mouse hosts, and (ii) self-renew, demonstrated by their ability to be serially transplanted. These properties suggest that CSCs are required for tumor maintenance and metastasis; thus, it has been predicted that CSC elimination is required for cure. This prediction has profoundly altered paradigms for cancer research, compelling investigators to prospectively isolate CSCs to characterize the molecular pathways regulating their behavior. Many potential strategies for CSC-directed therapy have been proposed, but few studies have rigorously demonstrated their efficacy using in vivo models. Herein, we highlight recent studies that demonstrate the utility of CSC-directed therapies and discuss the implications of the CSC hypothesis to experimental design and therapeutic strategies. Despite the many advances in our understanding of human cancer development, our ability to develop clinically effective therapies based on this knowledge has been met with limited success.1Vogelstein B Kinzler KW Cancer genes and the pathways they control.Nat Med. 2004; 10: 789-799Crossref PubMed Scopus (2494) Google Scholar,2Hanahan D Weinberg RA The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (15859) Google Scholar,3Fearon ER Vogelstein B A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (7792) Google Scholar Although conventional therapies frequently initially control tumor growth, most patients ultimately relapse. When the first molecularly targeted cancer therapy—imatinib—was developed to treat chronic myeloid leukemia (CML), there was great hope that such rationally based strategies would lead to cure, but the initial excitement has been tempered by the realization that imatinib does not effect cure.4Jones RJ Matsui WH Smith BD Cancer stem cells: are we missing the target?.J Natl Cancer Inst. 2004; 96: 583-585Crossref PubMed Google Scholar,5Huntly BJ Gilliland DG Cancer biology: summing up cancer stem cells.Nature. 2005; 435: 1169-1170Crossref PubMed Scopus (0) Google Scholar This result is not surprising since imatinib does not target the quiescent hematopoietic stem cells (HSCs) that harbor the characteristic BCR-ABL translocation of CML.6Graham SM Jørgensen HG Allan E Pearson C Alcorn MJ Richmond L et al.Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro.Blood. 2002; 99: 319-325Crossref PubMed Scopus (772) Google Scholar,7Hammond SM MicroRNAs as oncogenes.Curr Opin Genet Dev. 2006; 16: 4-9Crossref PubMed Scopus (0) Google Scholar,8Holtz MS Slovak ML Zhang F Sawyers CL Forman SJ Bhatia R Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation.Blood. 2002; 99: 3792-3800Crossref PubMed Scopus (0) Google Scholar These findings underscore the need to isolate self-renewing and therapy-resistant cancer cells as well as to determine the molecular pathways that regulate their biological behavior. Identification of such molecular pathways offers the best hope for developing curative cancer therapies. Over the past decade there have been extensive efforts to isolate cancer stem cells (CSCs) in solid and hematopoietic cancers (Table 1). Since the isolation and characterization of CSCs is the focus of numerous excellent review, we will focus instead on the data that address three predictions of the CSC hypothesis: (i) that CSCs are therapy-resistant cells; (ii) that CSC-directed therapies can effectively treat cancers; and (iii) that CSCs are relevant to both the biological behavior and clinical outcomes of cancers. Because experimental design is an important consideration when evaluating these data, we also discuss strategies for evaluating CSCs in each of these contexts.Table 1Selected CSCs identified in primary tumor isolatesTumorCSC phenotype% Tumor cells with CSC immunophenotypeTumors engrafting using sorted CSCs (1° Tx)Min. CSCs to engraft (1° Tx)Serial Tx performedMin. CSCs or bulk tumor cells for serial Tx (2° Tx)Ref.AMLCD34+CD38-0.1-1n/a2 × 105No—20Lapidot T Sirard C Vormoor J Murdoch B Hoang T Caceres-Cortes J et al.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.Nature. 1994; 367: 645-648Crossref PubMed Scopus (0) Google ScholarAMLCD34+CD38-0.02-215/185 × 103Yes2 × 105-2 × 10619Bonnet D Dick JE Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat Med. 1997; 3: 730-737Crossref PubMed Scopus (3853) Google ScholarBulkAMLCD34+CD38-n/a9/9103Yes103 CSCs69Ishikawa F Yoshida S Saito Y Hijikata A Kitamura H Tanaka S et al.Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region.Nat Biotechnol. 2007; 25: 1315-1321Crossref PubMed Scopus (421) Google ScholarBreastCD44+/CD24-/lowaLineage marker positive cells were also excluded.11-359/9100Pantel K Brakenhoff RH Brandt B Detection, clinical relevance and specific biological properties of disseminating tumour cells.Nat Rev Cancer. 2008; 8: 329-340Crossref PubMed Scopus (0) Google ScholarYesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.200 CSCs30Al-Hajj M Wicha MS Benito-Hernandez A Morrison SJ Clarke MF Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci USA. 2003; 100: 3983-3988Crossref PubMed Scopus (5730) Google ScholarMedullo-blastomaCD133+6-213/3104No—44Singh SK Hawkins C Clarke ID Squire JA Bayani J Hide T et al.Identification of human brain tumour initiating cells.Nature. 2004; 432: 396-401Crossref PubMed Scopus (4260) Google ScholarGlioblastomaCD133+19-294/4100Pantel K Brakenhoff RH Brandt B Detection, clinical relevance and specific biological properties of disseminating tumour cells.Nat Rev Cancer. 2008; 8: 329-340Crossref PubMed Scopus (0) Google ScholarYes103 CSCs44Singh SK Hawkins C Clarke ID Squire JA Bayani J Hide T et al.Identification of human brain tumour initiating cells.Nature. 2004; 432: 396-401Crossref PubMed Scopus (4260) Google ScholarHNSCCCD44+a0.1-42.713/255 × 103YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.2.5 × 104 CSCs38Prince ME Sivanandan R Kaczorowski A Wolf GT Kaplan MJ Dalerba P et al.Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma.Proc Natl Acad Sci USA. 2007; 104: 973-978Crossref PubMed Scopus (1241) Google ScholarColonCD133+1.8-24.511/17100Pantel K Brakenhoff RH Brandt B Detection, clinical relevance and specific biological properties of disseminating tumour cells.Nat Rev Cancer. 2008; 8: 329-340Crossref PubMed Scopus (0) Google ScholarYesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.100 CSCs47O'Brien CA Pollett A Gallinger S Dick JE A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.Nature. 2007; 445: 106-110Crossref PubMed Scopus (2515) Google ScholarColonCD133+0.7-6.112/181,500YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.n/a48Ricci-Vitiani L Lombardi DG Pilozzi E Biffoni M Todaro M Peschle C et al.Identification and expansion of human colon-cancer-initiating cells.Nature. 2007; 445: 111-115Crossref PubMed Scopus (2422) Google ScholarColonCD133+0.3-3.0n/a2.5-5 × 103Yesn/a48,49ColonESAhi/CD44+a0.03-38.06/6cTransplants were performed using CSCs purified from primary xenografts.200No—35Dalerba P Dylla SJ Park IK Liu R Wang X Cho RW et al.Phenotypic characterization of human colorectal cancer stem cells.Proc Natl Acad Sci USA. 2007; 104: 10158-10163Crossref PubMed Scopus (1179) Google ScholarESAhi/CD44+/CD166+a1.2-16.03/3150YesdP. Dalerba, personal communication.500 CSCsdP. Dalerba, personal communication.MelanomaABCB5+1.6-20.44/7105Yes104 CSCs53Schatton T Murphy GF Frank NY Yamaura K Waaga-Gasser AM Gasser M et al.Identification of cells initiating human melanomas.Nature. 2008; 451: 345-349Crossref PubMed Scopus (833) Google ScholarProstateCD44+0.1-20.02/2cTransplants were performed using CSCs purified from primary xenografts.103No—129Patrawala L Calhoun T Schneider-Broussard R Li H Bhatia B Tang S Reilly JG Chandra D Zhou J et al.Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells.Oncogene. 2006; 25: 1696-1708Crossref PubMed Scopus (629) Google ScholarPancreasCD44+CD24+ESA+0.2-0.810/10cTransplants were performed using CSCs purified from primary xenografts.100Pantel K Brakenhoff RH Brandt B Detection, clinical relevance and specific biological properties of disseminating tumour cells.Nat Rev Cancer. 2008; 8: 329-340Crossref PubMed Scopus (0) Google ScholarYesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.n/a36Li C Heidt DG Dalerba P Burant CF Zhang L Adsay V et al.Identification of pancreatic cancer stem cells.Cancer Res. 2007; 67: 1030-1037Crossref PubMed Scopus (1912) Google ScholarPancreasCD133+0.68-3.2111/11500YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.500 CSCs50Hermann PC Huber SL Herrler T Aicher A Ellwart JW Guba M et al.Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer.Cell Stem Cell. 2007; 1: 313-323Abstract Full Text Full Text PDF PubMed Scopus (1457) Google ScholarLung (non-small cell)CD133+0.32-22n/a1 × 104No—51Eramo A Lotti F Sette G Pilozzi E Biffoni M Di Virgilio A et al.Identification and expansion of the tumorigenic lung cancer stem cell population.Cell Death Differ. 2008; 15: 504-514Crossref PubMed Scopus (920) Google ScholarHepatocellularCD44+CD90+0.74-6.213/135,000YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.n/a39Yang ZF Ho DW Ng MN Lau CK Yu WC Ngai P et al.Significance of CD90+ cancer stem cells in human liver cancer.Cancer Cell. 2008; 13: 153-166Abstract Full Text Full Text PDF PubMed Scopus (640) Google ScholarB-ALLCD34+CD10-4.0-12.06/67 × 104Yes105 Bulk61Cox CV Evely RS Oakhill A Pamphilon DH Goulden NJ Blair A Characterization of acute lymphoblastic leukemia progenitor cells.Blood. 2004; 104: 2919-2925Crossref PubMed Scopus (0) Google ScholarCD34+CD19-2.0-4.05/55 × 104Yes105 BulkB-ALL (BCR-ABL+CD34+CD38-CD19+0.17-4.518/105.5 × 105-9 × 106YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.n/a46Castor A Nilsson L Astrand-Grundström I Buitenhuis M Ramirez C Anderson K et al.Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia.Nat Med. 2005; 11: 630-637Crossref PubMed Scopus (215) Google ScholarETV6/RUNX1+)T-ALLCD34+CD4-5.0-15.06/7104YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.3 × 104 Bulk62Cox CV Martin HM Kearns PR Virgo P Evely RS Blair A Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia.Blood. 2007; 109: 674-682Crossref PubMed Scopus (0) Google ScholarCD34+CD7-6.0-14.05/54 × 103YesbTertiary and/or quarternary transplants also performed in addition to secondary transplants.4 × 103 BulkMyelomaCD138-CD34-n/a1/1c1 × 106No—64Matsui W Huff CA Wang Q Malehorn MT Barber J Tanhehco Y et al.Characterization of clonogenic multiple myeloma cells.Blood. 2004; 103: 2332-2336Crossref PubMed Scopus (507) Google ScholarAbbreviations: 1°, primary; 2°, secondary; AML, acute myeloid leukemia; B-ALL, B-cell lymphoblastic leukemia; CSC, cancer stem cell; HNSCC, head-and-neck squamous cell carcinoma; Max, maximum; Min, minimum; n/a, not available; T-ALL, T-cell lymphoblastic leukemia; Tx, transplant.a Lineage marker positive cells were also excluded.b Tertiary and/or quarternary transplants also performed in addition to secondary transplants.c Transplants were performed using CSCs purified from primary xenografts.d P. Dalerba, personal communication. Open table in a new tab Abbreviations: 1°, primary; 2°, secondary; AML, acute myeloid leukemia; B-ALL, B-cell lymphoblastic leukemia; CSC, cancer stem cell; HNSCC, head-and-neck squamous cell carcinoma; Max, maximum; Min, minimum; n/a, not available; T-ALL, T-cell lymphoblastic leukemia; Tx, transplant. It has been appreciated for more than a century that tumors are composed of morphologically heterogeneous cells, and by the mid-twentieth century researchers understood that cancer cells also exhibit functional heterogeneity both in vitro9Price JE Tarin D Low incidence of tumourigenicity in agarose colonies from spontaneous murine mammary tumours.Differentiation. 1989; 41: 202-207Crossref PubMed Scopus (0) Google Scholar,10Gioanni J Farges MF Duplay H Hery M Zanghellini E Schneider M et al.In vitro clonogenicity in relation to kinetic and clinicopathological features of breast cancer.Bull Cancer. 1988; 75: 285-290PubMed Google Scholar,11Sabbath KD Ball ED Larcom P Davis RB Griffin JD Heterogeneity of clonogenic cells in acute myeloblastic leukemia.J Clin Invest. 1985; 75: 746-753Crossref PubMed Google Scholar,12Griffin JD Lowenberg B Clonogenic cells in acute myeloblastic leukemia.Blood. 1986; 68: 1185-1195PubMed Google Scholar and in vivo.13Bruce WR Van Der Gaag H A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo.Nature. 1963; 199: 79-80Crossref PubMed Scopus (0) Google Scholar,14Park CH Bergsagel DE McCulloch EA Mouse myeloma tumor stem cells: a primary cell culture assay.J Natl Cancer Inst. 1971; 46: 411-422PubMed Google Scholar,15Southam C Brunschwig A Quantitative studies of autotransplantation of human cancer.Cancer. 1961; 14: 463-481Crossref Google Scholar Despite this evidence for tumor cell functional heterogeneity, subsequent research emphasized the monoclonal nature of cancers with investigators reconciling tumor monoclonality with tumor heterogeneity by hypothesizing that the tumor microenvironment or the presence of clinically inapparent genetic subclones could explain the variable behavior of tumor cells.16Lagos-Quintana M Rauhut R Lendeckel W Tuschl T Identification of novel genes coding for small expressed RNAs.Science. 2001; 294: 853-858Crossref PubMed Scopus (2770) Google Scholar,17Dalerba P Cho RW Clarke MF Cancer stem cells: models and concepts.Annu Rev Med. 2007; 58: 267-284Crossref PubMed Scopus (750) Google Scholar In addition, the practical difficulties in obtaining primary tumor tissue for research as well as the relative ease of manipulating tumor cell lines promoted research that largely disregarded functional differences in tumor cell subsets. Although researchers had long-suspected that cancers may arise from stem or stem-like cells,18Wicha MS Liu S Dontu G Cancer stem cells: an old idea—a paradigm shift.Cancer Res. 2006; 66 (discussion 1895-1886): 1883-1890Crossref PubMed Scopus (0) Google Scholar it was not until the mid-1990s that a stem cell–like population was prospectively isolated from a human cancer. John Dick and colleagues showed that human acute myeloid leukemia (AML) contains a small percentage of cells (typically 0.1–1%) capable of transferring human AML into immunodeficient mouse hosts.19Bonnet D Dick JE Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat Med. 1997; 3: 730-737Crossref PubMed Scopus (3853) Google Scholar,20Lapidot T Sirard C Vormoor J Murdoch B Hoang T Caceres-Cortes J et al.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.Nature. 1994; 367: 645-648Crossref PubMed Scopus (0) Google Scholar The resulting leukemia recapitulates the morphologic and immunophenotypic heterogeneity of the original disease, and engrafted blasts can transfer disease into secondary recipients, formally establishing the presence of a self-renewing population. The leukemia-initiating cells, also known as leukemia stem cells (LSCs), could be FACS-purified by virtue of their cell surface phenotype (CD34+CD38−). Moreover, CD34+CD38+ cells did not engraft mice, consistent with a hierarchical organization in AML, with LSCs giving rise to non-LSCs, but not vice versa. Based on comparison of the immunophenotypes of LSCs to normal human HSCs and progenitors, it was predicted that AML LSCs arise from the earliest progenitors of the hematopoietic system.19Bonnet D Dick JE Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat Med. 1997; 3: 730-737Crossref PubMed Scopus (3853) Google Scholar,20Lapidot T Sirard C Vormoor J Murdoch B Hoang T Caceres-Cortes J et al.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.Nature. 1994; 367: 645-648Crossref PubMed Scopus (0) Google Scholar We had previously shown that human HSCs could be prospectively isolated from CD34+CD38lo cells based on the expression of CD90/Thy-1 (refs. 21Baum CM Weissman IL Tsukamoto AS Buckle AM Peault B Isolation of a candidate human hematopoietic stem-cell population.Proc Natl Acad Sci USA. 1992; 89: 2804-2808Crossref PubMed Google Scholar,22Negrin RS Atkinson K Leemhuis T Hanania E Juttner C Tierney K et al.Transplantation of highly purified CD34+Thy-1+ hematopoietic stem cells in patients with metastatic breast cancer.Biol Blood Marrow Transplant. 2000; 6: 262-271Abstract Full Text PDF PubMed Google Scholar) and that these cells were distinct from AML LSCs, which lack CD90 expression.23Miyamoto T Weissman IL Akashi K AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation.Proc Natl Acad Sci USA. 2000; 97: 7521-7526Crossref PubMed Scopus (0) Google Scholar These data suggest that AML LSCs are not likely to be derived from HSCs, but possibly from the recently described human multipotent progenitor.24Majeti R Park CY Weissman IL Identification of a Hierarchy of Multipotent Hematopoietic Progenitors in Human Cord Blood.Cell Stem Cell. 2007; 1: 635-645Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar,25Kondo M Wagers AJ Manz MG Prohaska SS Scherer DC Beilhack GF et al.Biology of hematopoietic stem cells and progenitors: implications for clinical application.Annu Rev Immunol. 2003; 21: 759-806Crossref PubMed Scopus (623) Google Scholar These seminal studies of AML LSCs laid the foundation for the CSC hypothesis which holds that, like normal tissue, cancers are maintained by a population of stem-like cells that exhibit the ability to self-renew as well as differentiate into downstream, non-self-renewing progenitors and mature cells.26Reya T Morrison SJ Clarke MF Weissman IL Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105-111Crossref PubMed Scopus (5442) Google Scholar Based on the studies identifying AML LSCs and other CSCs, a consensus definition for CSCs has been established, with a recent AACR workshop declaring that “cancer stem cells can only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor.”27Clarke MF Dick JE Dirks PB Eaves CJ Jamieson CH Jones DL et al.Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells.Cancer Res. 2006; 66: 9339-9344Crossref PubMed Scopus (1638) Google Scholar In practical terms, this means that a candidate CSC population should exhibit the following properties: (i) the unique ability to engraft; (ii) the ability to recapitulate the tumor of origin both morphologically and immunophenotypically in xenografts; and (iii) the ability to be serially transplanted. Experimental demonstration of CSC properties requires the use of xenotransplantation systems to demonstrate both tumor-initiating potential and the ability to be serially transplanted, the gold-standard for demonstrating self-renewal capacity.27Clarke MF Dick JE Dirks PB Eaves CJ Jamieson CH Jones DL et al.Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells.Cancer Res. 2006; 66: 9339-9344Crossref PubMed Scopus (1638) Google Scholar In our laboratory, CSCs are defined by transplantation of cancer cell subsets into immunodeficient mice, typically at orthotopic sites (e.g., breast to breast, brain to brain, marrow to marrow). In our experience, secondary transplants usually grow faster than primary grafts, and tertiary transplants grow even faster, likely representing enrichment for more aggressive subsets of CSCs. This reminds us that even CSCs are susceptible to selection pressures and that more aggressive tumors (and probably all metastases), likely represent the end-result of a competition among CSCs in a given tumor. As illustrated by the discovery of LSCs in AML, the characterization of stem and progenitor cells in normal tissue has expedited CSC isolation by providing candidate markers for purification of candidate CSC populations. Such prospective isolations of CSC allow their direct comparison to normal stem/progenitors, revealing important information about CSC regulation, CSC origins, and disease pathogenesis.26Reya T Morrison SJ Clarke MF Weissman IL Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105-111Crossref PubMed Scopus (5442) Google Scholar,28Weissman I Stem cell research: paths to cancer therapies and regenerative medicine.JAMA. 2005; 294: 1359-1366Crossref PubMed Scopus (0) Google Scholar For example, although LSCs in AML exhibit the human multipotent progenitor phenotype,24Majeti R Park CY Weissman IL Identification of a Hierarchy of Multipotent Hematopoietic Progenitors in Human Cord Blood.Cell Stem Cell. 2007; 1: 635-645Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar malignant cells in blast crisis of CML are Lin-CD34+CD38+CD45RA+ CD123+, corresponding to a normal human granulocyte-macrophage progenitor. Moreover, in blast crisis of CML, phenotypic granulocyte-macrophage progenitors show aberrant activation of the Wnt/β-catenin signaling pathway, a self-renewal associated pathway not active in normal granulocyte-macrophage progenitors.29Jamieson CH Ailles LE Dylla SJ Muijtjens M Jones C Zehnder JL et al.Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.N Engl J Med. 2004; 351: 657-667Crossref PubMed Scopus (1029) Google Scholar These data indicate that LSCs may arise from normal progenitor populations, and that aberrant activation of self-renewal pathways may be a part of this process. It is important to emphasize that the term “cancer stem cell” does not refer to the cell of origin. Instead, the term CSC refers to the properties shared with normal stem cells—self-renewal and the ability to initiate a hierarchy of more differentiated cells that cannot self-renew. Based on these properties, the CSC hypothesis makes two important predictions: (i) CSCs are required for tumor growth and metastasis; and, (ii) elimination of the CSCs is required for cure.26Reya T Morrison SJ Clarke MF Weissman IL Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105-111Crossref PubMed Scopus (5442) Google Scholar Based on observations in the clinic as well as in normal stem cells, some investigators have introduced an important corollary to these predictions—that CSCs are also relatively resistant to conventional therapy. Needless to say, these predictions have challenged investigators to isolate CSCs in all tumor types and identify the genes that regulate their function and responses to conventional therapies. Since the description of LSCs in AML, CSCs have been identified in numerous solid and hematopoietic cancers (Table 1). Although CSC populations have been described for numerous mouse cancer models and cell lines, we will largely limit our discussion to CSCs from primary human tumors. The first solid tumor CSC was isolated from breast cancer by Michael Clarke's group.30Al-Hajj M Wicha MS Benito-Hernandez A Morrison SJ Clarke MF Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci USA. 2003; 100: 3983-3988Crossref PubMed Scopus (5730) Google Scholar Although the normal human mammary stem cell still had not been isolated at the time of these studies, it had been appreciated that early multipotent epithelial progenitor cells express markers such as epithelial specific antigen (ESA) and CD44 (refs. 31Stingl J Eaves CJ Kuusk U Emerman JT Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast.Differentiation. 1998; 63: 201-213Crossref PubMed Scopus (0) Google Scholar,32Lee Y Kim M Han J Yeom KH Lee S Baek SH et al.MicroRNA genes are transcribed by RNA polymerase II.EMBO J. 2004; 23: 4051-4060Crossref PubMed Scopus (2155) Google Scholar,33Gudjonsson T Villadsen R Nielsen HL Ronnov-Jessen L Bissell MJ Petersen OW Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties.Genes Dev. 2002; 16: 693-706Crossref PubMed Scopus (254) Google Scholar,34Liu R Wang X Chen GY Dalerba P Gurney A Hoey T et al.The prognostic role of a gene signature from tumorigenic breast-cancer cells.N Engl J Med. 2007; 356: 217-226Crossref PubMed Scopus (681) Google Scholar). Using these markers, candidate CSC populations were isolated from dissociated primary breast tumors, FACS-purified, and transplanted into the mammary fat pads of NOD/SCID mice. Importantly, when separating tumor cells, a cocktail of lineage antibodies was used to exclude hematopoietic, mesenchymal, and endothelial components of the tumor. These studies showed that CD44+, CD24−/low cells were uniquely capable of transplanting disease to NOD/SCID mice. This population, representing 11–35% of cells in primary breast tumors, gave rise to tumors that recapitulated the morphologic and immunophenotypic features of the original tumor. In addition, these same cells could be sorted from the primary grafts and serially transplanted, demonstrating their self-renewal capacity. Since the description of the breast CSCs, numerous other solid tumor CSCs have been identified. Although the degree of rigor to which these populations were isolated differed both with respect to purity as well as their ability to serially transplant disease, they all fulfilled the CSC criteria established by the AACR. CSCs in colon,35Dalerba P Dylla SJ Park IK Liu R Wang X Cho RW et al.Phenotypic characterization of human colorectal cancer stem cells.Proc Natl Acad Sci USA. 2007; 104: 10158-10163Crossref PubMed Scopus (1179) Google Scholar pancreatic,36Li C Heidt DG Dalerba P Burant CF Zhang L Adsay V et al.Identification of pancreatic cancer stem cells.Cancer Res. 2007; 67: 1030-1037Crossref PubMed Scopus (1912) Google Scholar prostate,37Collins AT Berry PA Hyde C Stower MJ Maitland NJ Prospective identification of tumorigenic prostate cancer stem cells.Cancer Res. 2005; 65: 10946-10951Crossref PubMed Scopus (1753) Google Scholar and head-and-neck squamous cell38Prince ME Sivanandan R Kaczorowski A Wolf GT Kaplan MJ Dalerba P et al.Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma.Proc Natl Acad Sci USA. 2007; 104: 973-978Crossref PubMed Scopus (1241) Google Scholar carcinomas were enriched by virtue of their expression of CD44, a marker of progenitor cells in the basal layer of normal epithelium. Hepatocellular carcinoma CSCs were isolated based on the presence of CD90, a marker previously described on HSCs. This population could be further separated into highly tumorigenic and less-tumorigenic populations based on CD44 expression.39Yang ZF Ho DW Ng MN Lau CK Yu WC Ngai P et al.Significance of CD90+ cancer stem cells in human liver cancer.Cancer Cell. 2008; 13: 153-166Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar CD133, a marker previously shown to enrich for immature progenitors in normal hematopoietic, neural, endothelial and epithelial tissues,40Richardson GD Robson CN Lang SH Neal DE Maitland NJ Collins AT CD133, a novel marker for human prostatic epithelial stem cells.J Cell Sci. 2004; 117: 3539-3545Crossref PubMed Scopus (540) Google Scholar,41Yu S Zhang JZ Zhao CL Zhang HY Xu Q Isolation and characterization of the CD133+ precursors from the ventricular zone of human fetal brain by magnetic affinity cell sorting.Biotechnol Lett. 2004; 26: 1131-1136Crossref PubMed Scopus (24) Google Scholar,42Mizrak D Brittan M Alison MR CD133: molecule of the moment.J Pathol. 2008; 214: 3-9Crossref PubMed Scopus (377) Google Scholar was found to enrich tumor-initiating cells in glioblastoma and medulloblastoma,43Singh SK Clarke ID Terasaki M Bonn VE Hawki" @default.
• W2058172383 created "2016-06-24" @default.
• W2058172383 creator A5016145140 @default.
• W2058172383 creator A5049360628 @default.
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• W2058172383 date "2009-02-01" @default.
• W2058172383 modified "2023-10-03" @default.
• W2058172383 title "Cancer Stem Cell–Directed Therapies: Recent Data From the Laboratory and Clinic" @default.
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