Unravelling cancer stem cell potential (original) (raw)

• Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Leblond, C. P., Clermont, Y. & Nadler, N. J. The pattern of stem cell renewal in three epithelia. (esophagus, intestine and testis). Proc. Can. Cancer Conf. 7, 3–30 (1967).
  CAS PubMed Google Scholar
• Till, J. E. & McCulloch, E. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222 (1961).
  Article CAS PubMed Google Scholar
• Gallico, G. G. 3rd, O'Connor, N. E., Compton, C. C., Kehinde, O. & Green, H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N. Engl. J. Med. 311, 448–451 (1984).
  Article PubMed Google Scholar
• Rheinwald, J. G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6, 331–343 (1975).
  Article CAS PubMed Google Scholar
• Van Keymeulen, A. & Blanpain, C. Tracing epithelial stem cells during development, homeostasis, and repair. J. Cell Biol. 197, 575–584 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Pierce, G. B. & Dixon, F. J. Jr. Testicular teratomas. I. Demonstration of teratogenesis by metamorphosis of multipotential cells. Cancer 12, 573–583 (1959).
  Article CAS PubMed Google Scholar
• Pierce, G. B. Jr, Dixon, F. J. Jr & Verney, E. L. Teratocarcinogenic and tissue-forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest. 9, 583–602 (1960).
  PubMed Google Scholar
• Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Barrandon, Y. & Green, H. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl Acad. Sci. USA 84, 2302–2306 (1987).
  Article CAS PubMed PubMed Central Google Scholar
• Kobayashi, K., Rochat, A. & Barrandon, Y. Segregation of keratinocyte colony-forming cells in the bulge of the rat vibrissa. Proc. Natl Acad. Sci. USA 90, 7391–7395 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337 (1990).
  Article CAS PubMed Google Scholar
• Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K. & Barrandon, Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104, 233–245 (2001).
  Article CAS PubMed Google Scholar
• Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).
  Article CAS PubMed Google Scholar
• Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotech. 22, 411–417 (2004).
  Article CAS Google Scholar
• Jaks, V. et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature Genet. 40, 1291–1299 (2008).
  Article CAS PubMed Google Scholar
• Reynolds, B. A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992).
  Article CAS PubMed Google Scholar
• Pastrana, E., Silva-Vargas, V. & Doetsch, F. Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8, 486–498 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).
  Article CAS PubMed Google Scholar
• Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
  Article CAS PubMed Google Scholar
• Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010).
  Article CAS PubMed Google Scholar
• Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418.
• Jung, P. et al. Isolation and in vitro expansion of human colonic stem cells. Nature Med. 17, 1225–1227 (2011).
  Article CAS PubMed Google Scholar
• Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).
  Article CAS PubMed Google Scholar
• Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).
  Article CAS PubMed Google Scholar
• Ponti, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005).
  Article CAS PubMed Google Scholar
• Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J. & Maitland, N. J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).
  Article CAS PubMed Google Scholar
• Eramo, A. et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 15, 504–514 (2008).
  Article CAS PubMed Google Scholar
• Zhang, S. et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 68, 4311–4320 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Barrett, L. E. et al. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell 21, 11–24 (2012).
  Article CAS PubMed Google Scholar
• Schroeder, T. Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior. Cell Stem Cell 6, 203–207 (2010).
  Article CAS PubMed Google Scholar
• Purton, L. E. & Scadden, D. T. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 1, 263–270 (2007).
  Article CAS PubMed Google Scholar
• Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997).
  Article CAS PubMed Google Scholar
• Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).
  Article CAS PubMed Google Scholar
• Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).
  Article CAS PubMed Google Scholar
• Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl Acad. Sci. USA 105, 13427–13432 (2008).
  Article PubMed PubMed Central Google Scholar
• Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008).
  Article CAS PubMed Google Scholar
• Prince, M. E. 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 104, 973–978 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).
  Article CAS PubMed Google Scholar
• Curley, M. D. et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells 27, 2875–2883 (2009).
  CAS PubMed Google Scholar
• Valent, P. et al. Cancer stem cell definitions and terminology: the devil is in the details. Nature Rev. Cancer 12, 767–775 (2012).
  Article CAS Google Scholar
• Ishizawa, K. et al. Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 7, 279–282 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Schatton, T. et al. Identification of cells initiating human melanomas. Nature 451, 345–349 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Boiko, A. D. et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466, 133–137 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Luo, Y. et al. ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells 30, 2100–2113 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Civenni, G. et al. Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth. Cancer Res. 71, 3098–3109 (2011).
  Article CAS PubMed Google Scholar
• Lapouge, G. et al. Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness. EMBO J. 31, 4563–4575 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011).
  Article CAS PubMed Google Scholar
• Notta, F. et al. Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).
  Article CAS PubMed Google Scholar
• Clappier, E. et al. Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse. J. Exp. Med. 208, 653–661 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kreso, A. et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339, 543–548 (2013).
  Article CAS PubMed Google Scholar
• Dalerba, P. et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nature Biotech. 29, 1120–1127 (2011).
  Article CAS Google Scholar
• Schober, M. & Fuchs, E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc. Natl Acad. Sci. USA 108, 10544–10549 (2011).
  Article PubMed PubMed Central Google Scholar
• Curtis, S. J. et al. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell 7, 127–133 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Blanpain, C. Tracing the cellular origin of cancer. Nature Cell Biol. 15, 126–134 (2013).
  Article CAS PubMed Google Scholar
• Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).
  Article CAS PubMed Google Scholar
• Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
  Article CAS PubMed Google Scholar
• Mascre, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257–262 (2012).
  Article CAS PubMed Google Scholar
• Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).
  Article CAS PubMed Google Scholar
• Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).
  Article CAS PubMed Google Scholar
• Doupe, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093.
• Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012).
  Article CAS PubMed Google Scholar
• Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
  Article CAS PubMed Google Scholar
• Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet. 40, 915–920 (2008).
  Article CAS PubMed Google Scholar
• Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–607 (2009).
  Article CAS PubMed Google Scholar
• Batlle, E. et al. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251–263 (2002).
  Article CAS PubMed Google Scholar
• Merlos-Suarez, A. et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8, 511–524 (2011).
  Article CAS PubMed Google Scholar
• Kemper, K. et al. Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells 30, 2378–2386 (2012).
  Article CAS PubMed Google Scholar
• Gerbe, F., Brulin, B., Makrini, L., Legraverend, C. & Jay, P. DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology 137, 2179–2181 (2009).
  Article CAS PubMed Google Scholar
• Nakanishi, Y. et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nature Genet. 45, 98–103 (2012).
  Article CAS PubMed Google Scholar
• Zomer, A. et al. Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem Cells 31, 602–606 (2013).
  Article CAS PubMed Google Scholar
• Grosse-Gehling, P. et al. CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. J. Pathol. 229, 355–378 (2013).
  Article CAS PubMed Google Scholar
• Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998).
  Article CAS PubMed Google Scholar
• van de Wetering, M. et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).
  Article CAS PubMed Google Scholar
• Korinek, V. et al. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).
  Article CAS PubMed Google Scholar
• Morin, P. J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).
  Article CAS PubMed Google Scholar
• Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).
  Article CAS PubMed Google Scholar
• Youssef, K. K. et al. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation. Nature Cell Biol. 14, 1282–1294 (2012).
  Article CAS PubMed Google Scholar
• Yang, S. H. et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β3-catenin signaling. Nature Genet. 40, 1130–1135 (2008).
  Article CAS PubMed Google Scholar
• Spike, B. T. et al. A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer. Cell Stem Cell 10, 183–197 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Friedmann-Morvinski, D. et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338, 1080–1084 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
  Article CAS PubMed Google Scholar
• Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005).
  Article CAS PubMed Google Scholar
• Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).
  Article CAS PubMed Google Scholar
• Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006).
  Article CAS PubMed Google Scholar
• Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).
  Article CAS PubMed Google Scholar
• Lawson, D. A., Xin, L., Lukacs, R. U., Cheng, D. & Witte, O. N. Isolation and functional characterization of murine prostate stem cells. Proc. Natl Acad. Sci. USA 104, 181–186 (2007).
  Article CAS PubMed Google Scholar
• Ousset, M. et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nature Cell Biol. 14, 1131–1138 (2012).
  Article CAS PubMed Google Scholar
• Ito, M., Kizawa, K., Hamada, K. & Cotsarelis, G. Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen. Differentiation 72, 548–557 (2004).
  Article PubMed Google Scholar
• Buczacki, S. J. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65–69 (2013).
  Article CAS PubMed Google Scholar
• van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nature Cell Biol. 14, 1099–1104 (2012).
  Article CAS PubMed Google Scholar
• Quintana, E. et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510–523 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Fillmore, C. M. & Kuperwasser, C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 10, R25 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
  Article CAS PubMed Google Scholar
• Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, X. et al. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482, 529–533 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
  Article CAS PubMed Google Scholar
• Li, Y. M. et al. Upregulation of CXCR4 is essential for _HER2_-mediated tumor metastasis. Cancer Cell 6, 459–469 (2004).
  Article CAS PubMed Google Scholar
• Taichman, R. S. et al. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 62, 1832–1837 (2002).
  CAS PubMed Google Scholar
• Kim, M. et al. CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res. 70, 10411–10421 (2010).
  Article CAS PubMed Google Scholar
• Ramsey, D. M. & McAlpine, S. R. Halting metastasis through CXCR4 inhibition. Bioorg. Med. Chem. Lett. 23, 20–25 (2013).
  Article CAS PubMed Google Scholar
• Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).
  Article CAS PubMed Google Scholar
• Pang, R. et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6, 603–615 (2010).
  Article CAS PubMed Google Scholar
• Dieter, S. M. et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 9, 357–365 (2011).
  Article CAS PubMed Google Scholar
• Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004).
  Article CAS PubMed Google Scholar
• Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978).
  CAS PubMed Google Scholar
• Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001).
  Article CAS PubMed Google Scholar
• Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).
  Article CAS PubMed Google Scholar
• Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).
  Article CAS PubMed Google Scholar
• Shen, Q. et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289–300 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).
  Article CAS PubMed Google Scholar
• Beck, B. et al. A vascular niche and a VEGF–Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478, 399–403 (2011).
  CAS PubMed Google Scholar
• Hamerlik, P. et al. Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J. Exp. Med. 209, 507–520 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lanahan, A. et al. The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev. Cell 25, 156–168 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Butler, J. M. et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6, 251–264 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).
  Article CAS PubMed Google Scholar
• Chow, D. C., Wenning, L. A., Miller, W. M. & Papoutsakis, E. T. Modeling pO2 distributions in the bone marrow hematopoietic compartment. I. Krogh's model. Biophys. J. 81, 675–684 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Parmar, K., Mauch, P., Vergilio, J. A., Sackstein, R. & Down, J. D. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl Acad. Sci. USA 104, 5431–5436 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Semenza, G. L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Takubo, K. et al. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010).
  Article CAS PubMed Google Scholar
• Wang, Y., Liu, Y., Malek, S. N., Zheng, P. & Liu, Y. Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8, 399–411 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, H., Li, H., Xi, H. S. & Li, S. HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells. Blood 119, 2595–2607 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bar, E. E., Lin, A., Mahairaki, V., Matsui, W. & Eberhart, C. G. Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am. J. Pathol. 177, 1491–1502 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hashimoto, O. et al. Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1α-dependent manner in pancreatic cancer cells. Pathobiology 78, 181–192 (2011).
  Article CAS PubMed Google Scholar
• Soeda, A. et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α. Oncogene 28, 3949–3959 (2009).
  Article CAS PubMed Google Scholar
• Schwab, L. P. et al. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res. 14, R6 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Harrison, H. et al. Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ER-α status. Cancer Res. 73, 1420–1433 (2013).
  Article CAS PubMed Google Scholar
• Kuschel, A., Simon, P. & Tug, S. Functional regulation of HIF-1α under normoxia—is there more than post-translational regulation? J. Cell. Physiol. 227, 514–524 (2012).
  Article CAS PubMed Google Scholar
• Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nature Rev. Drug Discov. 10, 417–427 (2011).
  Article CAS Google Scholar
• Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012).
  Article CAS Google Scholar
• Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biol. 12, 468–476 (2010).
  Article CAS PubMed Google Scholar
• Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Sotiropoulou, P. A. et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nature Cell Biol. 12, 572–582 (2010).
  Article CAS PubMed Google Scholar
• Dylla, S. J. et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 3, e2428 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).
  Article CAS PubMed Google Scholar
• Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• de The, H. & Chen, Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nature Rev. Cancer 10, 775–783 (2010).
  Article CAS Google Scholar
• Piccirillo, S. G. et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761–765 (2006).
  Article CAS PubMed Google Scholar
• Sachlos, E. et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149, 1284–1297 (2012).
  Article CAS PubMed Google Scholar
• Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Gerrits, A. et al. Cellular barcoding tool for clonal analysis in the hematopoietic system. Blood 115, 2610–2618 (2010).
  Article CAS PubMed Google Scholar
• Lu, R., Neff, N. F., Quake, S. R. & Weissman, I. L. Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nature Biotech. 29, 928–933 (2011).
  Article CAS Google Scholar
• Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
  Article CAS PubMed Google Scholar
• Fernandes, K. J. et al. A dermal niche for multipotent adult skin-derived precursor cells. Nature Cell Biol. 6, 1082–1093 (2004).
  Article CAS PubMed Google Scholar
• Toma, J. G. et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature Cell Biol. 3, 778–784 (2001).
  Article CAS PubMed Google Scholar
• Hollier, B. G. et al. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 73, 1981–1992 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Morel, A. P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 3, e2888 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, Z. et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 69, 2400–2407 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Fan, F. et al. Overexpression of Snail induces epithelial–mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 1, 5–16 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Z. F. & Behringer, R. R. Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).
  Article CAS PubMed Google Scholar
• Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
  Article CAS PubMed Google Scholar
• Taube, J. H. et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl Acad. Sci. USA 107, 15449–15454 (2010).
  Article PubMed PubMed Central Google Scholar
• Ansieau, S. et al. Induction of EMT by Twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14, 79–89 (2008).
  Article CAS PubMed Google Scholar
• Yang, M. H. et al. Bmi1 is essential in _Twist1_-induced epithelial–mesenchymal transition. Nature Cell Biol. 12, 982–992 (2010).
  Article CAS PubMed Google Scholar
• Dhawan, S., Tschen, S. I. & Bhushan, A. Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation. Genes Dev. 23, 906–911 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene _bmi_-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).
  Article CAS PubMed Google Scholar
• Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).
  Article CAS PubMed Google Scholar
• Molofsky, A. V., He, S., Bydon, M., Morrison, S. J. & Pardal, R. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev. 19, 1432–1437 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).
  Article CAS PubMed PubMed Central Google Scholar