Skip to main content
Top
Published in: BioDrugs 5/2007

01-09-2007 | Mechanisms and Targets

Selective Targeting of Cancer Stem Cells

A New Concept in Cancer Therapeutics

Authors: Dr Hasan Korkaya, Max S. Wicha

Published in: BioDrugs | Issue 5/2007

Login to get access

Abstract

Although the concept of ‘cancer stem cell’ was first proposed more then a century ago, it has attracted a great deal of attention recently due to advances in stem cell biology, leading to the identification of these cells in a wide variety of human cancers. There is accumulating evidence that the resistance of cancer stem cells to many conventional therapies may account for the inability of these therapies to cure most metastatic cancers. The recent identification of stem cell markers and advances in stem cell biology have facilitated research in multiple aspects of cancer stem cell behavior. Stem cell subcomponents have now been identified in a number of human malignancies, including hematologic malignancies and tumors of the breast, prostate, brain, pancreas, head and neck, and colon. Furthermore, pathways that regulate self-renewal and cell fate in these systems are beginning to be elucidated. In addition to pathways such as Wnt, Notch and Hedgehog, known to regulate self-renewal of normal stem cells, tumor suppressor genes such as PTEN (phosphatase and tensin homolog on chromosome 10) and TP53 (tumor protein p53) have also been implicated in the regulation of cancer stem cell self-renewal. In cancer stem cells, these pathways are believed to be deregulated, leading to uncontrolled self-renewal of cancer stem cells which generate tumors that are resistant to conventional therapies. Current cancer therapeutics based on tumor regression may target and kill differentiated tumor cells, which compose the bulk of the tumor, while sparing the rare cancer stem cell population. The cancer stem cell model suggests that the design of new cancer therapeutics may require the targeting and elimination of cancer stem cells. Therefore, it is imperative to design new strategies based upon a better understanding of the signaling pathways that control aspects of self-renewal and survival in cancer stem cells in order to identify novel therapeutic targets in these cells.
Literature
2.
go back to reference Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea: a paradigm shift. Cancer Res 2006 Feb 15; 66 (4): 1883–90; discussion 96PubMedCrossRef Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea: a paradigm shift. Cancer Res 2006 Feb 15; 66 (4): 1883–90; discussion 96PubMedCrossRef
3.
go back to reference Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004 Sep 20; 23 (43): 7274–82PubMedCrossRef Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004 Sep 20; 23 (43): 7274–82PubMedCrossRef
4.
go back to reference Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001 Nov 1; 414 (6859): 105–11PubMedCrossRef Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001 Nov 1; 414 (6859): 105–11PubMedCrossRef
5.
6.
go back to reference Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007 Jan; 11 (1): 69–82PubMedCrossRef Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007 Jan; 11 (1): 69–82PubMedCrossRef
7.
go back to reference Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981 Jul 9; 292 (5819): 154–6PubMedCrossRef Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981 Jul 9; 292 (5819): 154–6PubMedCrossRef
8.
go back to reference Martin GR. Teratocarcinomas as a model system for the study of embryogenesis and neoplasia. Cell 1975 Jul; 5 (3): 229–43PubMedCrossRef Martin GR. Teratocarcinomas as a model system for the study of embryogenesis and neoplasia. Cell 1975 Jul; 5 (3): 229–43PubMedCrossRef
9.
go back to reference Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003 Apr 24; 422 (6934): 897–901PubMedCrossRef Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003 Apr 24; 422 (6934): 897–901PubMedCrossRef
10.
go back to reference Wagers AJ, Sherwood RI, Christensen JL, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002 Sep 27; 297 (5590): 2256–9PubMedCrossRef Wagers AJ, Sherwood RI, Christensen JL, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002 Sep 27; 297 (5590): 2256–9PubMedCrossRef
11.
go back to reference Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001 May 4; 105 (3): 369–77PubMedCrossRef Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001 May 4; 105 (3): 369–77PubMedCrossRef
12.
go back to reference Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994 Nov; 1 (8): 661–73PubMedCrossRef Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994 Nov; 1 (8): 661–73PubMedCrossRef
13.
go back to reference Baum CM, Weissman IL, Tsukamoto AS, et al. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A 1992 Apr 1; 89 (7): 2804–8PubMedCrossRef Baum CM, Weissman IL, Tsukamoto AS, et al. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A 1992 Apr 1; 89 (7): 2804–8PubMedCrossRef
14.
go back to reference Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988 Jul 1; 241 (4861): 58–62PubMedCrossRef Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988 Jul 1; 241 (4861): 58–62PubMedCrossRef
15.
go back to reference Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998 May; 125 (10): 1921–30PubMed Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998 May; 125 (10): 1921–30PubMed
16.
go back to reference Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006 Jan 5; 439 (7072): 84–8PubMedCrossRef Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006 Jan 5; 439 (7072): 84–8PubMedCrossRef
17.
go back to reference Zon LI. Developmental biology of hematopoiesis. Blood 1995 Oct 15; 86 (8): 2876–91PubMed Zon LI. Developmental biology of hematopoiesis. Blood 1995 Oct 15; 86 (8): 2876–91PubMed
18.
go back to reference Rossi DJ, Weissman IL. Pten, tumorigenesis, and stem cell self-renewal. Cell 2006 Apr 21; 125 (2): 229–31PubMedCrossRef Rossi DJ, Weissman IL. Pten, tumorigenesis, and stem cell self-renewal. Cell 2006 Apr 21; 125 (2): 229–31PubMedCrossRef
19.
go back to reference Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997 Jul; 3 (7): 730–7PubMedCrossRef Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997 Jul; 3 (7): 730–7PubMedCrossRef
20.
go back to reference Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004 Jul; 5 (7): 738–43PubMedCrossRef Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004 Jul; 5 (7): 738–43PubMedCrossRef
21.
go back to reference Lawson DA, Xin L, Lukacs R, et al. Prostate stem cells and prostate cancer. Cold Spring Harb Symp Quant Biol 2005; 70: 187–96PubMedCrossRef Lawson DA, Xin L, Lukacs R, et al. Prostate stem cells and prostate cancer. Cold Spring Harb Symp Quant Biol 2005; 70: 187–96PubMedCrossRef
22.
go back to reference Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004 Nov 18; 432 (7015): 396–401PubMedCrossRef Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004 Nov 18; 432 (7015): 396–401PubMedCrossRef
23.
go back to reference Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003 Apr 1; 100 (7): 3983–8PubMedCrossRef Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003 Apr 1; 100 (7): 3983–8PubMedCrossRef
24.
go back to reference Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007 Jan 4; 445 (7123): 111–5PubMedCrossRef Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007 Jan 4; 445 (7123): 111–5PubMedCrossRef
25.
go back to reference O’Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007 Jan 4; 445 (7123): 106–10PubMedCrossRef O’Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007 Jan 4; 445 (7123): 106–10PubMedCrossRef
26.
go back to reference Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007 Feb 1; 67 (3): 1030–7PubMedCrossRef Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007 Feb 1; 67 (3): 1030–7PubMedCrossRef
27.
go back to reference Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005 Jul 1; 65 (13): 5506–11PubMedCrossRef Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005 Jul 1; 65 (13): 5506–11PubMedCrossRef
28.
go back to reference Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003 May 15; 17 (10): 1253–70PubMedCrossRef Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003 May 15; 17 (10): 1253–70PubMedCrossRef
29.
go back to reference Miraglia S, Godfrey W, Yin AH, et al. A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 1997 Dec 15; 90 (12): 5013–21PubMed Miraglia S, Godfrey W, Yin AH, et al. A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 1997 Dec 15; 90 (12): 5013–21PubMed
30.
go back to reference Uchida N, Buck DW, He D, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A 2000 Dec 19; 97 (26): 14720–5PubMedCrossRef Uchida N, Buck DW, He D, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A 2000 Dec 19; 97 (26): 14720–5PubMedCrossRef
31.
go back to reference 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 U S A 2004 Jan 20; 101 (3): 781–6PubMedCrossRef 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 U S A 2004 Jan 20; 101 (3): 781–6PubMedCrossRef
32.
go back to reference Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatrie brain tumors. Proc Natl Acad Sci U S A 2003 Dec 9; 100 (25): 15178–83PubMedCrossRef Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatrie brain tumors. Proc Natl Acad Sci U S A 2003 Dec 9; 100 (25): 15178–83PubMedCrossRef
33.
go back to reference Ignatova TN, Kukekov VG, Laywell ED, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 2002 Sep; 39 (3): 193–206PubMedCrossRef Ignatova TN, Kukekov VG, Laywell ED, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 2002 Sep; 39 (3): 193–206PubMedCrossRef
34.
go back to reference Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003 Sep 15; 63 (18): 5821–8PubMed Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003 Sep 15; 63 (18): 5821–8PubMed
35.
go back to reference Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005 May 10; 102 (19): 6942–7PubMedCrossRef Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005 May 10; 102 (19): 6942–7PubMedCrossRef
36.
go back to reference Richardson GD, Robson CN, Lang SH, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 2004 Jul 15; 117 (Pt 16): 3539–45PubMedCrossRef Richardson GD, Robson CN, Lang SH, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 2004 Jul 15; 117 (Pt 16): 3539–45PubMedCrossRef
37.
go back to reference Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005 Jun 17; 121 (6): 823–35PubMedCrossRef Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005 Jun 17; 121 (6): 823–35PubMedCrossRef
38.
go back to reference Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005 Sep; 15 (9): 494–501PubMedCrossRef Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005 Sep; 15 (9): 494–501PubMedCrossRef
40.
go back to reference Sell S, Pierce GB. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest 1994 Jan; 70 (1): 6–22PubMed Sell S, Pierce GB. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest 1994 Jan; 70 (1): 6–22PubMed
41.
go back to reference Furth J. Recent studies on the etiology and nature of leukemia. Blood 1951 Nov; 6 (11): 964–75PubMed Furth J. Recent studies on the etiology and nature of leukemia. Blood 1951 Nov; 6 (11): 964–75PubMed
42.
go back to reference Burkert J, Wright NA, Alison MR. Stem cells and cancer: an intimate relationship. J Pathol 2006 Jul; 209 (3): 287–97PubMedCrossRef Burkert J, Wright NA, Alison MR. Stem cells and cancer: an intimate relationship. J Pathol 2006 Jul; 209 (3): 287–97PubMedCrossRef
43.
44.
go back to reference Bardin AJ, Le Borgne R, Schweisguth F. Asymmetric localization and function of cell-fate determinants: a fly’s view. Curr Opin Neurobiol 2004 Feb; 14 (1): 6–14PubMedCrossRef Bardin AJ, Le Borgne R, Schweisguth F. Asymmetric localization and function of cell-fate determinants: a fly’s view. Curr Opin Neurobiol 2004 Feb; 14 (1): 6–14PubMedCrossRef
45.
go back to reference Chia W, Yang X. Asymmetric division of Drosophila neural progenitors. Curr Opin Genet Dev 2002 Aug; 12 (4): 459–64PubMedCrossRef Chia W, Yang X. Asymmetric division of Drosophila neural progenitors. Curr Opin Genet Dev 2002 Aug; 12 (4): 459–64PubMedCrossRef
46.
go back to reference Caussinus E, Gonzalez C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 2005 Oct; 37 (10): 1125–9PubMedCrossRef Caussinus E, Gonzalez C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 2005 Oct; 37 (10): 1125–9PubMedCrossRef
47.
go back to reference Humbert P, Russell S, Richardson H. Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays 2003 Jun; 25 (6): 542–53PubMedCrossRef Humbert P, Russell S, Richardson H. Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays 2003 Jun; 25 (6): 542–53PubMedCrossRef
48.
go back to reference Gateff E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 1978 Jun 30; 200 (4349): 1448–59PubMedCrossRef Gateff E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 1978 Jun 30; 200 (4349): 1448–59PubMedCrossRef
49.
go back to reference Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980 Oct 30; 287 (5785): 795–801PubMedCrossRef Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980 Oct 30; 287 (5785): 795–801PubMedCrossRef
50.
go back to reference Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001 Dec 1; 15 (23): 3059–87PubMedCrossRef Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001 Dec 1; 15 (23): 3059–87PubMedCrossRef
51.
go back to reference Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003 Dec; 3 (12): 903–11CrossRef Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003 Dec; 3 (12): 903–11CrossRef
52.
go back to reference Dahmane N, Sanchez P, Gitton Y, et al. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 2001 Dec; 128 (24): 5201–12PubMed Dahmane N, Sanchez P, Gitton Y, et al. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 2001 Dec; 128 (24): 5201–12PubMed
53.
go back to reference Palma V, Ruiz i Altaba A. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 2004 Jan; 131 (2): 337–45PubMedCrossRef Palma V, Ruiz i Altaba A. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 2004 Jan; 131 (2): 337–45PubMedCrossRef
54.
go back to reference Palma V, Lim DA, Dahmane N, et al. Sonic Hedgehog controls stem cell behavior in the postnatal and adult brain. Development 2005 Jan; 132 (2): 335–44PubMedCrossRef Palma V, Lim DA, Dahmane N, et al. Sonic Hedgehog controls stem cell behavior in the postnatal and adult brain. Development 2005 Jan; 132 (2): 335–44PubMedCrossRef
55.
go back to reference Lai K, Kaspar BK, Gage FH, et al. Sonic Hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 2003 Jan; 6 (1): 21–7PubMedCrossRef Lai K, Kaspar BK, Gage FH, et al. Sonic Hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 2003 Jan; 6 (1): 21–7PubMedCrossRef
56.
go back to reference Machold R, Hayashi S, Rutlin M, et al. Sonic Hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003 Sep 11; 39 (6): 937–50PubMedCrossRef Machold R, Hayashi S, Rutlin M, et al. Sonic Hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003 Sep 11; 39 (6): 937–50PubMedCrossRef
57.
go back to reference Olsen CL, Hsu PP, Glienke J, et al. Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors. BMC Cancer 2004 Aug 4; 4: 43PubMedCrossRef Olsen CL, Hsu PP, Glienke J, et al. Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors. BMC Cancer 2004 Aug 4; 4: 43PubMedCrossRef
58.
go back to reference Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004 Oct 7; 431 (7009): 707–12PubMedCrossRef Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004 Oct 7; 431 (7009): 707–12PubMedCrossRef
59.
go back to reference Oro AE, Higgins KM, Hu Z, et al. Basal cell carcinomas in mice overexpressing Sonic Hedgehog. Science 1997 May 2; 276 (5313): 817–21PubMedCrossRef Oro AE, Higgins KM, Hu Z, et al. Basal cell carcinomas in mice overexpressing Sonic Hedgehog. Science 1997 May 2; 276 (5313): 817–21PubMedCrossRef
60.
go back to reference Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007 Jan 23; 17 (2): 165–72PubMedCrossRef Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007 Jan 23; 17 (2): 165–72PubMedCrossRef
61.
go back to reference Vestergaard J, Pedersen MW, Pedersen N, et al. Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro. Lung Cancer 2006 Jun; 52 (3): 281–90PubMedCrossRef Vestergaard J, Pedersen MW, Pedersen N, et al. Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro. Lung Cancer 2006 Jun; 52 (3): 281–90PubMedCrossRef
62.
go back to reference Douard R, Moutereau S, Pernet P, et al. Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery 2006 May; 139 (5): 665–70PubMedCrossRef Douard R, Moutereau S, Pernet P, et al. Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery 2006 May; 139 (5): 665–70PubMedCrossRef
63.
go back to reference Vorechovsky I, Benediktsson KP, Toftgard R. The patched/hedgehog/smoothened signalling pathway in human breast cancer: no evidence for HI 33Y SHH, PTCH and SMO mutations. Eur J Cancer 1999 May; 35 (5): 711–3PubMedCrossRef Vorechovsky I, Benediktsson KP, Toftgard R. The patched/hedgehog/smoothened signalling pathway in human breast cancer: no evidence for HI 33Y SHH, PTCH and SMO mutations. Eur J Cancer 1999 May; 35 (5): 711–3PubMedCrossRef
64.
go back to reference Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999 Feb 18; 397 (6720): 617–21PubMedCrossRef Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999 Feb 18; 397 (6720): 617–21PubMedCrossRef
65.
go back to reference Carpenter D, Stone DM, Brush J, et al. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci U S A 1998 Nov 10; 95 (23): 13630–4PubMedCrossRef Carpenter D, Stone DM, Brush J, et al. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci U S A 1998 Nov 10; 95 (23): 13630–4PubMedCrossRef
66.
go back to reference Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002 May; 2 (5): 361–72CrossRef Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002 May; 2 (5): 361–72CrossRef
67.
go back to reference Ruiz i Altaba A, Palma V, Dahmane N. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 2002 Jan; 3 (1): 24–33CrossRef Ruiz i Altaba A, Palma V, Dahmane N. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 2002 Jan; 3 (1): 24–33CrossRef
68.
go back to reference Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006 Jun 15; 66 (12): 6063–71PubMedCrossRef Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006 Jun 15; 66 (12): 6063–71PubMedCrossRef
69.
go back to reference Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science 1987 Apr 3; 236 (4797): 70–3PubMedCrossRef Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science 1987 Apr 3; 236 (4797): 70–3PubMedCrossRef
70.
go back to reference Nilsson M, Unden AB, Krause D, et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A 2000 Mar 28; 97 (7): 3438–43PubMedCrossRef Nilsson M, Unden AB, Krause D, et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A 2000 Mar 28; 97 (7): 3438–43PubMedCrossRef
71.
go back to reference Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Glil and the Sonic Hedgehog signalling pathway in skin tumours. Nature 1997 Oct 23; 389 (6653): 876–81PubMedCrossRef Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Glil and the Sonic Hedgehog signalling pathway in skin tumours. Nature 1997 Oct 23; 389 (6653): 876–81PubMedCrossRef
72.
go back to reference Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003 Oct 23; 425 (6960): 851–6PubMedCrossRef Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003 Oct 23; 425 (6960): 851–6PubMedCrossRef
73.
go back to reference Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985 Dec; 43 (3 Pt 2): 567–81PubMedCrossRef Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985 Dec; 43 (3 Pt 2): 567–81PubMedCrossRef
74.
go back to reference Jen WC, Wettstein D, Turner D, et al. The Notch ligand, X-Delta-2, mediates segmentation of the paraxial mesoderm in Xenopus embryos. Development 1997 Mar; 124 (6): 1169–78PubMed Jen WC, Wettstein D, Turner D, et al. The Notch ligand, X-Delta-2, mediates segmentation of the paraxial mesoderm in Xenopus embryos. Development 1997 Mar; 124 (6): 1169–78PubMed
75.
go back to reference Lindsell CE, Shawber CJ, Boulter J, et al. Jagged: a mammalian ligand that activates Notchl. Cell 1995 Mar 24; 80 (6): 909–17PubMedCrossRef Lindsell CE, Shawber CJ, Boulter J, et al. Jagged: a mammalian ligand that activates Notchl. Cell 1995 Mar 24; 80 (6): 909–17PubMedCrossRef
76.
go back to reference Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 2002; 25: 471–90PubMedCrossRef Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 2002; 25: 471–90PubMedCrossRef
77.
go back to reference Solecki DJ, Liu XL, Tomoda T, et al. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 2001 Aug 30; 31 (4): 557–68PubMedCrossRef Solecki DJ, Liu XL, Tomoda T, et al. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 2001 Aug 30; 31 (4): 557–68PubMedCrossRef
78.
go back to reference Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006 Aug 17; 442 (7104): 823–6PubMedCrossRef Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006 Aug 17; 442 (7104): 823–6PubMedCrossRef
79.
80.
go back to reference Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006 Aug 1; 66 (15): 7445–52PubMedCrossRef Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006 Aug 1; 66 (15): 7445–52PubMedCrossRef
81.
go back to reference Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004 Oct 8; 306 (5694): 269–71PubMedCrossRef Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004 Oct 8; 306 (5694): 269–71PubMedCrossRef
82.
go back to reference Hallahan AR, Pritchard JI, Hansen S, et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of Sonic Hedgehog-induced medulloblastomas. Cancer Res 2004 Nov 1; 64 (21): 7794–800PubMedCrossRef Hallahan AR, Pritchard JI, Hansen S, et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of Sonic Hedgehog-induced medulloblastomas. Cancer Res 2004 Nov 1; 64 (21): 7794–800PubMedCrossRef
83.
go back to reference Fang TC, Alison MR, Wright NA, et al. Adult stem cell plasticity: will engineered tissues be rejected? Int J Exp Pathol 2004 Jun; 85 (3): 115–24PubMedCrossRef Fang TC, Alison MR, Wright NA, et al. Adult stem cell plasticity: will engineered tissues be rejected? Int J Exp Pathol 2004 Jun; 85 (3): 115–24PubMedCrossRef
84.
go back to reference Dontu G, Jackson KW, McNicholas E, et al. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 2004; 6 (6): R605–15PubMedCrossRef Dontu G, Jackson KW, McNicholas E, et al. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 2004; 6 (6): R605–15PubMedCrossRef
85.
go back to reference Smith GH, Gallahan D, Diella F, et al. Constitutive expression of a truncated INT3 gene in mouse mammary epithelium impairs differentiation and functional development. Cell Growth Differ 1995 May; 6 (5): 563–77PubMed Smith GH, Gallahan D, Diella F, et al. Constitutive expression of a truncated INT3 gene in mouse mammary epithelium impairs differentiation and functional development. Cell Growth Differ 1995 May; 6 (5): 563–77PubMed
86.
go back to reference Uyttendaele H, Soriano JV, Montesano R, et al. Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Dev Biol 1998 Apr 15; 196 (2): 204–17PubMedCrossRef Uyttendaele H, Soriano JV, Montesano R, et al. Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Dev Biol 1998 Apr 15; 196 (2): 204–17PubMedCrossRef
87.
go back to reference Soriano JV, Uyttendaele H, Kitajewski J, et al. Expression of an activated Notch-4 (int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro. Int J Cancer 2000 Jun 1; 86 (5): 652–9PubMedCrossRef Soriano JV, Uyttendaele H, Kitajewski J, et al. Expression of an activated Notch-4 (int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro. Int J Cancer 2000 Jun 1; 86 (5): 652–9PubMedCrossRef
88.
go back to reference Nicolas M, Wolfer A, Raj K, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet 2003 Mar; 33 (3): 416–21PubMedCrossRef Nicolas M, Wolfer A, Raj K, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet 2003 Mar; 33 (3): 416–21PubMedCrossRef
89.
go back to reference Gonzalez-Sancho JM, Aguilera O, Garcia JM, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene 2005 Feb 3; 24 (6): 1098–103PubMedCrossRef Gonzalez-Sancho JM, Aguilera O, Garcia JM, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene 2005 Feb 3; 24 (6): 1098–103PubMedCrossRef
91.
go back to reference Kelly OG, Pinson KI, Skarnes WC. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 2004 Jun; 131 (12): 2803–15PubMedCrossRef Kelly OG, Pinson KI, Skarnes WC. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 2004 Jun; 131 (12): 2803–15PubMedCrossRef
92.
go back to reference Huelsken J, Vogel R, Brinkmann V, et al. Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 2000 Feb 7; 148 (3): 567–78PubMedCrossRef Huelsken J, Vogel R, Brinkmann V, et al. Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 2000 Feb 7; 148 (3): 567–78PubMedCrossRef
93.
go back to reference Li Y, Welm B, Podsypanina K, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 2003 Dec 23; 100 (26): 15853–8PubMedCrossRef Li Y, Welm B, Podsypanina K, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 2003 Dec 23; 100 (26): 15853–8PubMedCrossRef
94.
go back to reference Lindvall C, Evans NC, Zylstra CR, et al. The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis. J Biol Chem 2006 Nov 17; 281 (46): 35081–7PubMedCrossRef Lindvall C, Evans NC, Zylstra CR, et al. The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis. J Biol Chem 2006 Nov 17; 281 (46): 35081–7PubMedCrossRef
95.
go back to reference Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 2002 Jun 1; 115 (Pt 11): 2381–8PubMed Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 2002 Jun 1; 115 (Pt 11): 2381–8PubMed
96.
go back to reference van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002 Oct 18; 111 (2): 241–50PubMedCrossRef van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002 Oct 18; 111 (2): 241–50PubMedCrossRef
97.
go back to reference Batlle E, Henderson JT, Beghtel H, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ ephrinB. Cell 2002 Oct 18; 111 (2): 251–63PubMedCrossRef Batlle E, Henderson JT, Beghtel H, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ ephrinB. Cell 2002 Oct 18; 111 (2): 251–63PubMedCrossRef
98.
go back to reference Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 2003 Jul 15; 17 (14): 1709–13PubMedCrossRef Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 2003 Jul 15; 17 (14): 1709–13PubMedCrossRef
99.
go back to reference He XC, Zhang J, Li L. Cellular and molecular regulation of hematopoietic and intestinal stem cell behavior. Ann NY Acad Sci 2005 May; 1049: 28–38PubMedCrossRef He XC, Zhang J, Li L. Cellular and molecular regulation of hematopoietic and intestinal stem cell behavior. Ann NY Acad Sci 2005 May; 1049: 28–38PubMedCrossRef
100.
go back to reference Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001 Jun; 28 (2): 184–7PubMedCrossRef Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001 Jun; 28 (2): 184–7PubMedCrossRef
101.
go back to reference Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003 May 22; 423 (6938): 409–14PubMedCrossRef Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003 May 22; 423 (6938): 409–14PubMedCrossRef
102.
go back to reference Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997 Apr; 15 (4): 356–62PubMedCrossRef Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997 Apr; 15 (4): 356–62PubMedCrossRef
103.
go back to reference Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997 Mar 28; 275 (5308): 1943–7PubMedCrossRef Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997 Mar 28; 275 (5308): 1943–7PubMedCrossRef
104.
go back to reference Teng DH, Hu R, Lin H, et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997 Dec 1; 57 (23): 5221–5PubMed Teng DH, Hu R, Lin H, et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997 Dec 1; 57 (23): 5221–5PubMed
105.
go back to reference Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997 Sep 15; 57 (18): 3935–40PubMed Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997 Sep 15; 57 (18): 3935–40PubMed
106.
go back to reference Garcia JM, Silva JM, Dominguez G, et al. Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res Treat 1999 Oct; 57 (3): 237–43PubMedCrossRef Garcia JM, Silva JM, Dominguez G, et al. Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res Treat 1999 Oct; 57 (3): 237–43PubMedCrossRef
107.
go back to reference Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 1999 Apr 13; 96 (8): 4240–5PubMedCrossRef Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 1999 Apr 13; 96 (8): 4240–5PubMedCrossRef
108.
go back to reference Fang X, Yu SX, Lu Y, et al. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A 2000 Oct 24; 97 (22): 11960–5PubMedCrossRef Fang X, Yu SX, Lu Y, et al. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A 2000 Oct 24; 97 (22): 11960–5PubMedCrossRef
109.
go back to reference Monick MM, Carter AB, Robeff PK, et al. Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of beta-catenin. J Immunol 2001 Apr 1; 166 (7): 4713–20PubMed Monick MM, Carter AB, Robeff PK, et al. Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of beta-catenin. J Immunol 2001 Apr 1; 166 (7): 4713–20PubMed
110.
go back to reference Perez-Tenorio G, Stal O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002 Feb 12; 86 (4): 540–5PubMedCrossRef Perez-Tenorio G, Stal O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002 Feb 12; 86 (4): 540–5PubMedCrossRef
111.
go back to reference Shoman N, Klassen S, McFadden A, et al. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol 2005 Feb; 18 (2): 250–9PubMedCrossRef Shoman N, Klassen S, McFadden A, et al. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol 2005 Feb; 18 (2): 250–9PubMedCrossRef
112.
go back to reference Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004 Aug; 6 (2): 117–27PubMedCrossRef Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004 Aug; 6 (2): 117–27PubMedCrossRef
113.
go back to reference Schmitz M, Grignard G, Margue C, et al. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer 2007 Mar 15; 120 (6): 1284–92PubMedCrossRef Schmitz M, Grignard G, Margue C, et al. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer 2007 Mar 15; 120 (6): 1284–92PubMedCrossRef
114.
go back to reference Wang S, Garcia AJ, Wu M, et al. Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci U S A 2006 Jan 31; 103 (5): 1480–5PubMedCrossRef Wang S, Garcia AJ, Wu M, et al. Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci U S A 2006 Jan 31; 103 (5): 1480–5PubMedCrossRef
115.
go back to reference Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006 May 25; 441 (7092): 518–22PubMedCrossRef Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006 May 25; 441 (7092): 518–22PubMedCrossRef
116.
go back to reference Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006 May 25; 441 (7092): 475–82PubMedCrossRef Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006 May 25; 441 (7092): 475–82PubMedCrossRef
117.
go back to reference He XC, Yin T, Grindley JC, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 2007 Feb; 39 (2): 189–98PubMedCrossRef He XC, Yin T, Grindley JC, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 2007 Feb; 39 (2): 189–98PubMedCrossRef
118.
go back to reference Molofsky AV, He S, Bydon M, et al. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the pl6Ink4a and pl9Arf senescence pathways. Genes Dev 2005 Jun 15; 19 (12): 1432–7PubMedCrossRef Molofsky AV, He S, Bydon M, et al. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the pl6Ink4a and pl9Arf senescence pathways. Genes Dev 2005 Jun 15; 19 (12): 1432–7PubMedCrossRef
119.
go back to reference Molofsky AV, Pardal R, Morrison SJ. Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 2004 Dec; 16 (6): 700–7PubMedCrossRef Molofsky AV, Pardal R, Morrison SJ. Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 2004 Dec; 16 (6): 700–7PubMedCrossRef
120.
go back to reference Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 2003 Feb; 13 (1): 77–83PubMedCrossRef Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 2003 Feb; 13 (1): 77–83PubMedCrossRef
121.
go back to reference Scadden DTC, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000 Mar 10; 287 (5459): 1804–8PubMedCrossRef Scadden DTC, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000 Mar 10; 287 (5459): 1804–8PubMedCrossRef
122.
go back to reference Soussi T, Kato S, Levy PP, et al. Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 2005 Jan; 25 (1): 6–17PubMedCrossRef Soussi T, Kato S, Levy PP, et al. Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 2005 Jan; 25 (1): 6–17PubMedCrossRef
124.
go back to reference Aladjem MI, Spike BT, Rodewald LW, et al. ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr Biol 1998 Jan 29; 8 (3): 145–55PubMedCrossRef Aladjem MI, Spike BT, Rodewald LW, et al. ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr Biol 1998 Jan 29; 8 (3): 145–55PubMedCrossRef
125.
go back to reference Lin T, Chao C, Saito S, et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 2005 Feb; 7 (2): 165–71PubMedCrossRef Lin T, Chao C, Saito S, et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 2005 Feb; 7 (2): 165–71PubMedCrossRef
126.
go back to reference Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003 May 30; 113 (5): 631–42PubMedCrossRef Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003 May 30; 113 (5): 631–42PubMedCrossRef
127.
go back to reference Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003 May 30; 113 (5): 643–55PubMedCrossRef Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003 May 30; 113 (5): 643–55PubMedCrossRef
128.
go back to reference Meletis K, Wirta V, Hede SM, et al. p53 suppresses the self-renewal of adult neural stem cells. Development 2006 Jan; 133 (2): 363–9PubMedCrossRef Meletis K, Wirta V, Hede SM, et al. p53 suppresses the self-renewal of adult neural stem cells. Development 2006 Jan; 133 (2): 363–9PubMedCrossRef
129.
go back to reference Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003 May 15; 423 (6937): 302–5PubMedCrossRef Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003 May 15; 423 (6937): 302–5PubMedCrossRef
130.
go back to reference Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004 Nov; 114 (9): 1299–307PubMed Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004 Nov; 114 (9): 1299–307PubMed
131.
go back to reference Zindy F, Quelle DE, Roussel MF, et al. Expression of the pl6INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 1997 Jul 10; 15 (2): 203–11PubMedCrossRef Zindy F, Quelle DE, Roussel MF, et al. Expression of the pl6INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 1997 Jul 10; 15 (2): 203–11PubMedCrossRef
132.
go back to reference Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006 Sep 28; 443 (7110): 421–6PubMed Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006 Sep 28; 443 (7110): 421–6PubMed
133.
go back to reference Molofsky AV, Slutsky SG, Joseph NM, et al. Increasing pl6INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006 Sep 28; 443 (7110): 448–52PubMedCrossRef Molofsky AV, Slutsky SG, Joseph NM, et al. Increasing pl6INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006 Sep 28; 443 (7110): 448–52PubMedCrossRef
134.
go back to reference Gunther EJ, Moody SE, Belka GK, et al. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev 2003 Feb 15; 17 (4): 488–501PubMedCrossRef Gunther EJ, Moody SE, Belka GK, et al. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev 2003 Feb 15; 17 (4): 488–501PubMedCrossRef
135.
go back to reference Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007 Feb 8; 445 (7128): 656–60PubMedCrossRef Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007 Feb 8; 445 (7128): 656–60PubMedCrossRef
136.
go back to reference Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007 Feb 8; 445 (7128): 661–5PubMedCrossRef Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007 Feb 8; 445 (7128): 661–5PubMedCrossRef
137.
go back to reference Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004 Jul; 51 (1): 1–28PubMedCrossRef Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004 Jul; 51 (1): 1–28PubMedCrossRef
138.
139.
go back to reference Bruserud O, Gjertsen BT. New strategies for the treatment of acute myelogenous leukemia: differentiation induction: present use and future possibilities. Stem Cells 2000; 18 (3): 157–65PubMedCrossRef Bruserud O, Gjertsen BT. New strategies for the treatment of acute myelogenous leukemia: differentiation induction: present use and future possibilities. Stem Cells 2000; 18 (3): 157–65PubMedCrossRef
140.
go back to reference Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997 Oct 9; 337 (15): 1021–8PubMedCrossRef Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997 Oct 9; 337 (15): 1021–8PubMedCrossRef
141.
go back to reference Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. European APL 91 Group. Blood 1993 Dec 1; 82 (11): 3241–9PubMed Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. European APL 91 Group. Blood 1993 Dec 1; 82 (11): 3241–9PubMed
142.
go back to reference Ding W, Li YP, Nobile LM, et al. Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARalpha fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy. Blood 1998 Aug 15; 92 (4): 1172–83PubMed Ding W, Li YP, Nobile LM, et al. Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARalpha fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy. Blood 1998 Aug 15; 92 (4): 1172–83PubMed
143.
go back to reference Zhou DC, Kim SH, Ding W, et al. Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood 2002 Feb 15; 99 (4): 1356–63PubMedCrossRef Zhou DC, Kim SH, Ding W, et al. Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood 2002 Feb 15; 99 (4): 1356–63PubMedCrossRef
144.
go back to reference Emionite L, Galmozzi F, Grattarolav M, et al. Histone deacetylase inhibitors enhance retinoid response in human breast cancer cell lines. Anticancer Res 2004 Nov–Dec; 24 (6): 4019–24PubMed Emionite L, Galmozzi F, Grattarolav M, et al. Histone deacetylase inhibitors enhance retinoid response in human breast cancer cell lines. Anticancer Res 2004 Nov–Dec; 24 (6): 4019–24PubMed
145.
go back to reference Chen JK, Taipale J, Cooper MK, et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002 Nov 1; 16 (21): 2743–8PubMedCrossRef Chen JK, Taipale J, Cooper MK, et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002 Nov 1; 16 (21): 2743–8PubMedCrossRef
146.
go back to reference Mimeault M, Moore E, Moniaux N, 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 2006 Feb 15; 118 (4): 1022–31PubMedCrossRef Mimeault M, Moore E, Moniaux N, 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 2006 Feb 15; 118 (4): 1022–31PubMedCrossRef
147.
go back to reference Kubo M, Nakamura M, Tasaki A, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004 Sep 1; 64 (17): 6071–4PubMedCrossRef Kubo M, Nakamura M, Tasaki A, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004 Sep 1; 64 (17): 6071–4PubMedCrossRef
148.
go back to reference Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002 Aug 30; 297 (5586): 1559–61PubMedCrossRef Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002 Aug 30; 297 (5586): 1559–61PubMedCrossRef
149.
go back to reference Sanchez P, Hernandez AM, Stecca B, et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci U S A 2004 Aug 24; 101 (34): 12561–6PubMedCrossRef Sanchez P, Hernandez AM, Stecca B, et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci U S A 2004 Aug 24; 101 (34): 12561–6PubMedCrossRef
150.
go back to reference Watkins DN, Berman DM, Baylin SB. Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell Cycle 2003 May–Jun; 2 (3): 196–8PubMedCrossRef Watkins DN, Berman DM, Baylin SB. Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell Cycle 2003 May–Jun; 2 (3): 196–8PubMedCrossRef
151.
go back to reference Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003 Oct 23; 425 (6960): 846–51PubMedCrossRef Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003 Oct 23; 425 (6960): 846–51PubMedCrossRef
152.
go back to reference Sanchez P, Ruiz i Altaba A. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev 2005 Feb; 122 (2): 223–30PubMedCrossRef Sanchez P, Ruiz i Altaba A. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev 2005 Feb; 122 (2): 223–30PubMedCrossRef
153.
go back to reference Weijzen S, Rizzo P, Braid M, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 2002 Sep; 8 (9): 979–86PubMedCrossRef Weijzen S, Rizzo P, Braid M, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 2002 Sep; 8 (9): 979–86PubMedCrossRef
154.
go back to reference Pece S, Serresi M, Santolini E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 2004 Oct 25; 167 (2): 215–21PubMedCrossRef Pece S, Serresi M, Santolini E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 2004 Oct 25; 167 (2): 215–21PubMedCrossRef
155.
go back to reference Pollard M, Luckert PH. Indomethacin treatment of rats with dimethylhydrazine-induced intestinal tumors. Cancer Treat Rep 1980; 64 (12): 1323–7PubMed Pollard M, Luckert PH. Indomethacin treatment of rats with dimethylhydrazine-induced intestinal tumors. Cancer Treat Rep 1980; 64 (12): 1323–7PubMed
156.
157.
go back to reference He TC, Chan TA, Vogelstein B, et al. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999 Oct 29; 99 (3): 335–45PubMedCrossRef He TC, Chan TA, Vogelstein B, et al. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999 Oct 29; 99 (3): 335–45PubMedCrossRef
158.
go back to reference Eisinger AL, Prescott SM, Jones DA, et al. The role of cyclooxygenase-2 and prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat 2007 Jan; 82 (1–4): 147–54PubMedCrossRef Eisinger AL, Prescott SM, Jones DA, et al. The role of cyclooxygenase-2 and prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat 2007 Jan; 82 (1–4): 147–54PubMedCrossRef
159.
go back to reference Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004 Jan; 5 (1): 91–102PubMedCrossRef Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004 Jan; 5 (1): 91–102PubMedCrossRef
160.
go back to reference Shah NM, Groves AK, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 1996 May 3; 85 (3): 331–43PubMedCrossRef Shah NM, Groves AK, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 1996 May 3; 85 (3): 331–43PubMedCrossRef
161.
go back to reference Piccirillo SG, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006 Dec 7; 444 (7120): 761–5PubMedCrossRef Piccirillo SG, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006 Dec 7; 444 (7120): 761–5PubMedCrossRef
162.
go back to reference Yu K, Toral-Barza L, Discafani C, et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001 Sep; 8 (3): 249–58PubMedCrossRef Yu K, Toral-Barza L, Discafani C, et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001 Sep; 8 (3): 249–58PubMedCrossRef
163.
go back to reference Frost P, Moatamed F, Hoang B, et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004 Dec 15; 104 (13): 4181–7PubMedCrossRef Frost P, Moatamed F, Hoang B, et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004 Dec 15; 104 (13): 4181–7PubMedCrossRef
164.
go back to reference Vassilev LT. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 2004 Apr; 3 (4): 419–21PubMedCrossRef Vassilev LT. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 2004 Apr; 3 (4): 419–21PubMedCrossRef
165.
go back to reference Ding K, Lu Y, Nikolovska-Coleska Z, et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2006 Jun 15; 49 (12): 3432–5PubMedCrossRef Ding K, Lu Y, Nikolovska-Coleska Z, et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 2006 Jun 15; 49 (12): 3432–5PubMedCrossRef
166.
go back to reference Bendall LJ, Bradstock KF, Gottlieb DJ. Expression of CD44 variant exons in acute myeloid leukemia is more common and more complex than that observed in normal blood, bone marrow or CD34+ cells. Leukemia 2000 Jul; 14 (7): 1239–46PubMedCrossRef Bendall LJ, Bradstock KF, Gottlieb DJ. Expression of CD44 variant exons in acute myeloid leukemia is more common and more complex than that observed in normal blood, bone marrow or CD34+ cells. Leukemia 2000 Jul; 14 (7): 1239–46PubMedCrossRef
167.
go back to reference Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006 Oct; 12 (10): 1167–74PubMedCrossRef Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006 Oct; 12 (10): 1167–74PubMedCrossRef
Metadata
Title
Selective Targeting of Cancer Stem Cells
A New Concept in Cancer Therapeutics
Authors
Dr Hasan Korkaya
Max S. Wicha
Publication date
01-09-2007
Publisher
Springer International Publishing
Published in
BioDrugs / Issue 5/2007
Print ISSN: 1173-8804
Electronic ISSN: 1179-190X
DOI
https://doi.org/10.2165/00063030-200721050-00002

Other articles of this Issue 5/2007

BioDrugs 5/2007 Go to the issue

Adis Drug Profile

Rituximab