Tumour-initiating cells: challenges and opportunities for anticancer drug discovery (original) (raw)

• Gilman, A. The initial clinical trial of nitrogen mustard. Am. J. Surg. 105, 574–578 (1963).
  Article CAS PubMed Google Scholar
• Kohn, K. W. Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment — fifteenth Bruce F. Cain Memorial Award Lecture. Cancer Res. 56, 5533–5546 (1996).
  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
• 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
• Singh, S. K. et al. Identification of human brain tumour-initiating cells. Nature 432, 396–401 (2004). References 4 and 5 provide an early description of the purification of tumour-initiating cells that give rise to solid malignancies.
  Article CAS PubMed 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
• Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).
  Article CAS PubMed Google Scholar
• Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).
  Article CAS PubMed Google Scholar
• Schatton, T. et al. Identification of cells initiating human melanomas. Nature 451, 345–349 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, Z. F. et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13, 153–166 (2008).
  Article CAS PubMed Google Scholar
• Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
  Article CAS PubMed Google Scholar
• Pardal, R., Clarke, M. F. & Morrison, S. J. Applying the principles of stem-cell biology to cancer. Nature Rev. Cancer 3, 895–902 (2003).
  Article CAS Google Scholar
• Clarke, M. F. et al. Cancer stem cells — perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006b).
  Article CAS PubMed Google Scholar
• Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L. & Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007). This paper described the observation that three mouse models of leukaemia and lymphoma are maintained by a dominant tumour cell population. The authors posit that xenotransplantation may select for tumour cells that are capable of surviving in a foreign environment.
  Article CAS PubMed 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
• Kennedy, J. A., Barabe, F., Poeppl, A. G., Wang, J. C. & Dick, J. E. Comment on “Tumor growth need not be driven by rare cancer stem cells”. Science 318, 1722 (2007); author reply 318, 1722 (2007).
  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). The original report that showed the existence of stem cells in leukaemia.
  Article CAS PubMed Google Scholar
• Wang, J. C. et al. High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 91, 2406–2414 (1998).
  Article CAS PubMed Google Scholar
• Miyamoto, T., Weissman, I. L. & Akashi, K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc. Natl Acad. Sci. USA 97, 7521–7526 (2000). This study showed that purified populations of leukaemia stem cells contained the identical translocation as that found in their progeny, the blast cells, suggesting that the clonal progression to cancer could operate through the 'stem cell compartment'.
  Article CAS PubMed PubMed Central Google Scholar
• Hill, R. P. Identifying cancer stem cells in solid tumors: case not proven. Cancer Res. 66, 1891–1895; discussion 1890 (2006).
  Article CAS PubMed Google Scholar
• Haug, J. S. et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell 2, 367–379 (2008).
  Article CAS PubMed Google Scholar
• Chen, G. Y., Tang, J., Zheng, P. & Liu, Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323, 1722–1725 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zeppernick, F. et al. Stem cell marker CD133 affects clinical outcome in glioma patients. Clin. Cancer Res. 14, 123–129 (2008).
  Article CAS PubMed Google Scholar
• So, C. W. et al. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 3, 161–171 (2003).
  Article CAS PubMed Google Scholar
• Jaiswal, S. et al. Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Proc. Natl Acad. Sci. USA 100, 10002–10007 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).
  Article CAS PubMed Google Scholar
• Liu, J. C., Deng, T., Lehal, R. S., Kim, J. & Zacksenhaus, E. Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-induced mammary tumors. Cancer Res. 67, 8671–8681 (2007a).
• Cho, R. W. et al. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26, 364–371 (2008).
  Article CAS PubMed Google Scholar
• Read, T. A. et al. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15, 135–147 (2009).
  Article CAS PubMed PubMed Central 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
• Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–607 (2009). References 30 and 31 described lineage-tracing experiments using transgenic models that can bypass the limitations and experimental variability of the transplantation assay.
  Article CAS PubMed Google Scholar
• Ward, R. J. et al. Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma. Cancer Res. 69, 4682–4690 (2009).
  Article CAS PubMed Google Scholar
• The Cancer Genome Atlas Research network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
• Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Warner, J. K., Wang, J. C., Hope, K. J., Jin, L. & Dick, J. E. Concepts of human leukemic development. Oncogene 23, 7164–7177 (2004).
  Article CAS PubMed Google Scholar
• Hess, A. R., Margaryan, N. V., Seftor, E. A. & Hendrix, M. J. Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis: role of the Eph receptors. Dev. Dyn. 236, 3283–3296 (2007).
  Article CAS PubMed Google Scholar
• Beachy, P. A., Karhadkar, S. S. & Berman, D. M. Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324–331 (2004).
  Article CAS PubMed Google Scholar
• Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).
  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
• Zhao, C. et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12, 528–541 (2007).
  Article CAS 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). This paper described different requirements for Wnt signalling in cutaneous tumour-initiating cells and normal stem cells.
  Article CAS PubMed Google Scholar
• Peacock, C. D. et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl Acad. Sci. USA 104, 4048–4053 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).
  Article CAS PubMed Google Scholar
• Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).
  Article CAS PubMed Google Scholar
• Akala, O. O. et al. Long-term haematopoietic reconstitution by Trp53−/− p16Ink4a−/−p19Arf−/− multipotent progenitors. Nature 453, 228–232 (2008).
  Article CAS PubMed Google Scholar
• Wu, M. et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541–554 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Guan, Y., Gerhard, B. & Hogge, D. E. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 101, 3142–3149 (2003).
  Article CAS PubMed Google Scholar
• Holyoake, T., Jiang, X., Eaves, C. & Eaves, A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 94, 2056–2064 (1999).
  Article CAS PubMed Google Scholar
• Yang, Z. J. et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135–145 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• He, X. C. et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nature Genet. 39, 189–198 (2007).
  Article CAS PubMed Google Scholar
• Ashkenazi, R., Gentry, S. N. & Jackson, T. L. Pathways to tumorigenesis — modeling mutation acquisition in stem cells and their progeny. Neoplasia 10, 1170–1182 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells — an integrated concept of malignant tumour progression. Nature Rev. Cancer 5, 744–749 (2005).
  Article CAS Google Scholar
• Balic, M. et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin. Cancer Res. 12, 5615–5621 (2006).
  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
• Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002).
  Article CAS Google Scholar
• Eger, A. et al. β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 23, 2672–2680 (2004).
  Article CAS PubMed Google Scholar
• Timmerman, L. A. et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99–115 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).
  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
• Moore, K. A. & Lemischka, I. R. Stem cells and their niches. Science 311, 1880–1885 (2006).
  Article CAS PubMed Google Scholar
• Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).
  Article CAS PubMed Google Scholar
• Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).
  Article CAS PubMed Google Scholar
• Li, L. & Neaves, W. B. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 66, 4553–4557 (2006).
  Article CAS PubMed Google Scholar
• Bissell, M. J. & Labarge, M. A. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 7, 17–23 (2005).
  CAS PubMed PubMed Central Google Scholar
• Walkley, C. R. et al. A microenvironment-induced myeloproliferative syndrome caused by RARγ deficiency. Cell 129, 1097–1110 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005).
  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
• Hambardzumyan, D. et al. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 22, 436–448 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bao, S. et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848 (2006).
  Article CAS PubMed Google Scholar
• Clarke, M. F. & Becker, M. W. Stem cells: the real culprits in cancer? Sci. Am. 295, 52–59 (2006).
  Article PubMed Google Scholar
• Singh, S. K., Clarke, I. D., Hide, T. & Dirks, P. B. Cancer stem cells in nervous system tumors. Oncogene 23, 7267–7273 (2004).
  Article CAS PubMed Google Scholar
• Al-Hajj, M., Becker, M. W., Wicha, M., Weissman, I. & Clarke, M. F. Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47 (2004).
  Article CAS PubMed Google Scholar
• van Rhenen, A. et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin. Cancer Res. 11, 6520–6527 (2005).
  Article CAS PubMed Google Scholar
• Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007).
  Article CAS PubMed Google Scholar
• Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).
  Article CAS PubMed Google Scholar
• Gottesman, M. M. Mechanisms of cancer drug resistance. Annu. Rev. Med. 53, 615–627 (2002).
  Article CAS PubMed Google Scholar
• Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Med. 7, 1028–1034 (2001).
  Article CAS PubMed Google Scholar
• Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).
  Article CAS PubMed 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
• Potten, C. S., Wilson, J. W. & Booth, C. Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 15, 82–93 (1997).
  Article CAS PubMed Google Scholar
• Era, T. Bcr-Abl is a “molecular switch” for the decision for growth and differentiation in hematopoietic stem cells. Int. J. Hematol. 76, 35–43 (2002).
  Article CAS PubMed Google Scholar
• Bedi, A. et al. BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia. Blood 81, 2898–2902 (1993).
  Article CAS PubMed Google Scholar
• Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).
  Article CAS PubMed Google Scholar
• Hughes, T. P. et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 349, 1423–1432 (2003).
  Article CAS PubMed Google Scholar
• Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701–4707 (2003).
  Article CAS PubMed Google Scholar
• Hamilton, A. et al. BCR-ABL activity and its response to drugs can be determined in CD34+ CML stem cells by CrkL phosphorylation status using flow cytometry. Leukemia 20, 1035–1039 (2006).
  Article CAS PubMed Google Scholar
• Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008).
  Article CAS PubMed Google Scholar
• Huff, C. A., Matsui, W., Smith, B. D. & Jones, R. J. The paradox of response and survival in cancer therapeutics. Blood 107, 431–434 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Wicha, M. S., Liu, S. & Dontu, G. Cancer stem cells: an old idea — a paradigm shift. Cancer Res. 66, 1883–1890; discussion 1895–1986 (2006).
  Article CAS PubMed Google Scholar
• Korkaya, H., Paulson, A., Iovino, F. & Wicha, M. S. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27, 6120–6130 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Magnifico, A. et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin. Cancer Res. 15, 2010–2021 (2009).
  Article CAS PubMed Google Scholar
• Nahta, R., Yu, D., Hung., M. C., Hortobagyi, G. N. & Esteva, F. J. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nature Clin. Pract. Oncol. 3, 269–280 (2006).
  Article CAS Google Scholar
• Jordan, C. T. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 4, 203–205 (2009). An excellent review discussing the issues and misconceptions in the cancer stem cell field.
  Article CAS PubMed PubMed Central Google Scholar
• Hogan, B. L. et al. Branching morphogenesis of the lung: new models for a classical problem. Cold Spring Harb. Symp. Quant. Biol. 62, 249–256 (1997).
  Article CAS PubMed Google Scholar
• Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).
  Article CAS PubMed Google Scholar
• Kawano, Y. & Kypta, R. Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 116, 2627–2634 (2003).
  Article CAS PubMed Google Scholar
• Suzuki, H. et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nature Genet. 36, 417–422 (2004).
  Article CAS PubMed Google Scholar
• Lepourcelet, M. et al. Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex. Cancer Cell 5, 91–102 (2004).
  Article CAS PubMed Google Scholar
• Emami, K. H. et al. A small molecule inhibitor of β-catenin/CREB-binding protein transcription [corrected]. Proc. Natl Acad. Sci. USA 101, 12682–12687 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• You, L. et al. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res. 64, 5385–5389 (2004).
  Article CAS PubMed Google Scholar
• You, L. et al. Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells. Oncogene 23, 6170–6174 (2004).
  Article CAS PubMed Google Scholar
• Sanchez, P. et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl Acad. Sci. USA 101, 12561–12566 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/− p53−/− mice. Cancer Cell 6, 229–240 (2004).
  Article CAS PubMed Google Scholar
• Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003).
  Article CAS PubMed Google Scholar
• Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Watkins, D. N. et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003).
  Article CAS PubMed Google Scholar
• Athar, M. et al. Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res. 64, 7545–7552 (2004).
  Article CAS PubMed Google Scholar
• Lee, J. et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391–403 (2006).
  Article CAS PubMed Google Scholar
• Sasai, K. et al. Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res. 66, 4215–4222 (2006).
  Article CAS PubMed Google Scholar
• Fan, L. et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145, 3961–3970 (2004).
  Article CAS PubMed Google Scholar
• Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406–410 (2008).
  Article CAS PubMed Google Scholar
• Weijzen, S. et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Med. 8, 979–986 (2002).
  Article CAS PubMed Google Scholar
• Bocchetta, M., Miele, L., Pass, H. I. & Carbone, M. Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells. Oncogene 22, 81–89 (2003).
  Article CAS PubMed Google Scholar
• Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).
  Article CAS PubMed Google Scholar
• van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).
  Article CAS PubMed Google Scholar
• Fan, X. et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 66, 7445–7452 (2006).
  Article CAS PubMed Google Scholar
• Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).
  Article CAS PubMed Google Scholar
• Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006).
  Article CAS PubMed Google Scholar
• Li, K. et al. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J. Biol. Chem. 283, 8046–8054 (2008).
  Article CAS PubMed Google Scholar
• Guzman, M. L. et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl Acad. Sci. USA 99, 16220–16225 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Diamandis, P. et al. Chemical genetics reveals a complex functional ground state of neural stem cells. Nature Chem. Biol. 3, 268–273 (2007).
  Article CAS Google Scholar
• Ayyanan, A. et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc. Natl Acad. Sci. USA 103, 3799–3804 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Palomero, T. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nature Med. 13, 1203–1210 (2007).
  Article CAS PubMed 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). References 118 and 127 describe differentiation as a strategy to combat tumour-initiating cells.
  Article CAS PubMed Google Scholar
• Cozzio, A. et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 17, 3029–3035 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nature Rev. Cancer 6, 846–856 (2006).
  Article CAS Google Scholar
• Lee, J. et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13, 69–80 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bracken, A. P. et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Gonzalez, M. E. et al. Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene 28, 843–853 (2009).
  Article CAS PubMed Google Scholar
• Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).
  Article CAS PubMed Google Scholar
• Zhou, J. et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc. Natl Acad. Sci. USA 104, 16158–16163 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Viale, A. et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457, 51–56 (2009).
  Article CAS PubMed Google Scholar
• Zhou, B. B. & Elledge, S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).
  Article CAS PubMed Google Scholar
• Evan, G. I. The ever-lengthening arm of p53. Cancer Cell 14, 108–110 (2008).
  Article CAS PubMed Google Scholar
• Godar, S. et al. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62–73 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Blair, A., Hogge, D. E., Ailles, L. E., Lansdorp, P. M. & Sutherland, H. J. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 89, 3104–3112 (1997).
  Article CAS PubMed Google Scholar
• Blair, A. & Sutherland, H. J. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp. Hematol. 28, 660–671 (2000).
  Article CAS PubMed Google Scholar
• Jordan, C. T. et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777–1784 (2000).
  Article CAS PubMed Google Scholar
• Adams, G. P. & Weiner, L. M. Monoclonal antibody therapy of cancer. Nature Biotech. 23, 1147–1157 (2005).
  Article CAS Google Scholar
• Kawasaki, B. T., Mistree, T., Hurt, E. M., Kalathur, M. & Farrar, W. L. Co-expression of the toleragenic glycoprotein, CD200, with markers for cancer stem cells. Biochem. Biophys. Res. Commun. 364, 778–782 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, A. M. & Senter, P. D. Arming antibodies: prospects and challenges for immunoconjugates. Nature Biotech. 23, 1137–1146 (2005).
  Article CAS Google Scholar
• Burges, A. et al. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study. Clin. Cancer Res. 13, 3899–3905 (2007).
  Article CAS PubMed Google Scholar
• Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C. & Gottesman, M. M. Targeting multidrug resistance in cancer. Nature Rev. Drug Discov. 5, 219–234 (2006).
  Article CAS Google Scholar
• Ishikawa, F. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nature Biotech. 25, 1315–1321 (2007).
  Article CAS Google Scholar
• Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Med. 12, 1167–1174 (2006).
  Article CAS PubMed 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
• 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
• Capela, A. & Temple, S. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35, 865–875 (2002).
  Article PubMed Google Scholar
• Louissaint, A. Jr, Rao, S., Leventhal, C. & Goldman, S. A. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945–960 (2002).
  Article CAS PubMed Google Scholar
• Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).
  Article CAS PubMed Google Scholar
• Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (2006).
  Article CAS PubMed Google Scholar
• Molckovsky, A. & Siu, L. L. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology meeting. J. Hematol. Oncol. 1, 20 (2008).
  Article PubMed PubMed Central Google Scholar
• Cullion, K. et al. Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 24, 6172–6181 (2009).
  Article CAS Google Scholar
• Mimeault, M. et al. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int. J. Cancer 118, 1022–1031 (2006).
  Article CAS PubMed Google Scholar
• Riobo, N. A., Lu, K., Ai, X., Haines, G. M. & Emerson, C. P. Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc. Natl Acad. Sci. USA 103, 4505–4510 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072–1078 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bleau, A. M. et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4, 226–235 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jimeno, A. et al. A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol. Cancer Ther. 8, 310–314 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kondo, T., Setoguchi, T. & Taga, T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc. Natl Acad. Sci. USA 101, 781–786 (2004).
  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 PubMed PubMed Central CAS Google Scholar
• Charafe-Jauffret, E. et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 69, 1302–1313 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hirschmann-Jax, C. et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc. Natl Acad. Sci. USA 101, 14228–14233 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Patrawala, L. et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res. 65, 6207–6219 (2005).
  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
• Pollard, S. M. et al. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 4, 568–580 (2009).
  Article CAS PubMed Google Scholar
• Ginestier, C. et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555–567 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).
  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
• Ince, T. A. et al. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12, 160–170 (2007).
  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
• Underhill, G. H. & Bhatia, S. N. High-throughput analysis of signals regulating stem cell fate and function. Curr. Opin. Chem. Biol. 11, 357–366 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172–180 (2001).
  Article CAS Google Scholar
• Androutsellis-Theotokis, A. et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823–826 (2006).
  Article CAS PubMed Google Scholar
• Ezashi, T., Das, P. & Roberts, R. M. Low O2 tensions and the prevention of differentiation of hES cells. Proc. Natl Acad. Sci. USA 102, 4783–4788 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Olivotto, M. & Dello Sbarba, P. Environmental restrictions within tumor ecosystems select for a convergent, hypoxia-resistant phenotype of cancer stem cells. Cell Cycle 7, 176–187 (2008).
  Article CAS PubMed Google Scholar
• Chen, S. et al. Self-renewal of embryonic stem cells by a small molecule. Proc. Natl Acad. Sci. USA 103, 17266–17271 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Desbordes, S. C. et al. High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. Cell Stem Cell 2, 602–612 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Falk, A., Karlsson, T. E., Kurdija, S., Frisen, J. & Zupicich, J. High-throughput identification of genes promoting neuron formation and lineage choice in mouse embryonic stem cells. Stem Cells 25, 1539–1545 (2007).
  Article CAS PubMed Google Scholar
• Saxe, J. P. et al. A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation. Chem. Biol. 14, 1019–1030 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bushway, P. J. & Mercola, M. High-throughput screening for modulators of stem cell differentiation. Methods Enzymol. 414, 300–316 (2006).
  Article CAS PubMed Google Scholar
• Ungrin, M. D., Joshi, C., Nica, A., Bauwens, C. & Zandstra, P. W. Reproducible, ultra high-throughput formation of multicellular organization from single cell suspension-derived human embryonic stem cell aggregates. PLoS ONE 3, e1565 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Kim, K. H. et al. Three-dimensional tissue cytometer based on high-speed multiphoton microscopy. Cytometry A 71, 991–1002 (2007).
  Article PubMed Google Scholar
• Mazurier, F., Gan, O. I., McKenzie, J. L., Doedens, M. & Dick, J. E. Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment. Blood 103, 545–552 (2004).
  Article CAS PubMed Google Scholar
• Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kern, S. E. & Shibata, D. The fuzzy math of solid tumor stem cells: a perspective. Cancer Res. 67, 8985–8988 (2007).
  Article CAS PubMed Google Scholar
• Galli, R. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004).
  Article CAS PubMed Google Scholar
• McKenzie, J. L., Gan, O. I., Doedens, M. & Dick, J. E. Human short-term repopulating stem cells are efficiently detected following intrafemoral transplantation into NOD/SCID recipients depleted of CD122+ cells. Blood 106, 1259–1261 (2005).
  Article CAS PubMed Google Scholar
• Shimosato, Y. et al. Transplantation of human tumors in nude mice. J. Natl Cancer Inst. 56, 1251–1260 (1976).
  Article CAS PubMed Google Scholar
• Anderson, S. A. et al. Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 105, 420–425 (2005).
  Article CAS PubMed Google Scholar
• Vlashi, E. et al. In vivo imaging, tracking, and targeting of cancer stem cells. J. Natl Cancer Inst. 101, 350–359 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Xie, Y. et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97–101 (2009).
  Article CAS PubMed Google Scholar
• Abraham, B. K. et al. Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin. Cancer Res. 11, 1154–1159 (2005).
  CAS PubMed Google Scholar
• Liu, R. et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356, 217–226 (2007).
  Article CAS PubMed Google Scholar
• Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Weinstein, I. B. Cancer. Addiction to oncogenes — the Achilles heal of cancer. Science 297, 63–64 (2002).
  Article CAS PubMed Google Scholar
• Tabs, S. & Avci, O. Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur. J. Dermatol. 14, 96–102 (2004).
  PubMed Google Scholar
• Marangoni, E. et al. CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts. Br. J. Cancer 100, 918–922 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
  Article CAS PubMed Google Scholar
• Beier, D. et al. CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67, 4010–4015 (2007).
  Article CAS PubMed Google Scholar
• Barabe, F., Kennedy, J. A., Hope, K. J. & Dick, J. E. Modeling the initiation and progression of human acute leukemia in mice. Science 316, 600–604 (2007).
  Article CAS PubMed Google Scholar
• Sausville, E. A. & Burger, A. M. Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 66, 3351–3354, (2006).
  Article CAS PubMed Google Scholar