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.
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References
Nilsson S. Tumor starters: stem cells eyed as anti-cancer target. ABC News [online]. Available from URL: http://www.netscape.com/viewstory/2006/11/27/tumor-starters-stem-cells-eyed-as-anti-cancer-target/ [Accessed 2007 Jul 23]
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 96
Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004 Sep 20; 23 (43): 7274–82
Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001 Nov 1; 414 (6859): 105–11
Scadden DT. The stem-cell niche as an entity of action. Nature 2006 Jun 29; 441 (7097): 1075–9
Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007 Jan; 11 (1): 69–82
Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981 Jul 9; 292 (5819): 154–6
Martin GR. Teratocarcinomas as a model system for the study of embryogenesis and neoplasia. Cell 1975 Jul; 5 (3): 229–43
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): 897–901
Wagers AJ, Sherwood RI, Christensen JL, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002 Sep 27; 297 (5590): 2256–9
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): 369–77
Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994 Nov; 1 (8): 661–73
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): 2804–8
Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988 Jul 1; 241 (4861): 58–62
Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998 May; 125 (10): 1921–30
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): 84–8
Zon LI. Developmental biology of hematopoiesis. Blood 1995 Oct 15; 86 (8): 2876–91
Rossi DJ, Weissman IL. Pten, tumorigenesis, and stem cell self-renewal. Cell 2006 Apr 21; 125 (2): 229–31
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): 730–7
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): 738–43
Lawson DA, Xin L, Lukacs R, et al. Prostate stem cells and prostate cancer. Cold Spring Harb Symp Quant Biol 2005; 70: 187–96
Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004 Nov 18; 432 (7015): 396–401
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): 3983–8
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007 Jan 4; 445 (7123): 111–5
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): 106–10
Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007 Feb 1; 67 (3): 1030–7
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): 5506–11
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): 1253–70
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): 5013–21
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): 14720–5
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): 781–6
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): 15178–83
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): 193–206
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): 5821–8
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): 6942–7
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): 3539–45
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): 823–35
Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005 Sep; 15 (9): 494–501
Guo W, Lasky JL, Wu H. Cancer stem cells. Pediatr Res 2006 Apr; 59 (4 Pt 2): 59R–64R
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): 6–22
Furth J. Recent studies on the etiology and nature of leukemia. Blood 1951 Nov; 6 (11): 964–75
Burkert J, Wright NA, Alison MR. Stem cells and cancer: an intimate relationship. J Pathol 2006 Jul; 209 (3): 287–97
Clevers H. Stem cells, asymmetric division and cancer. Nat Genet 2005 Oct; 37 (10): 1027–8
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): 6–14
Chia W, Yang X. Asymmetric division of Drosophila neural progenitors. Curr Opin Genet Dev 2002 Aug; 12 (4): 459–64
Caussinus E, Gonzalez C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 2005 Oct; 37 (10): 1125–9
Humbert P, Russell S, Richardson H. Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays 2003 Jun; 25 (6): 542–53
Gateff E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 1978 Jun 30; 200 (4349): 1448–59
Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980 Oct 30; 287 (5785): 795–801
Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001 Dec 1; 15 (23): 3059–87
Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003 Dec; 3 (12): 903–11
Dahmane N, Sanchez P, Gitton Y, et al. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 2001 Dec; 128 (24): 5201–12
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): 337–45
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): 335–44
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): 21–7
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): 937–50
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: 43
Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004 Oct 7; 431 (7009): 707–12
Oro AE, Higgins KM, Hu Z, et al. Basal cell carcinomas in mice overexpressing Sonic Hedgehog. Science 1997 May 2; 276 (5313): 817–21
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): 165–72
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): 281–90
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): 665–70
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): 711–3
Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999 Feb 18; 397 (6720): 617–21
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): 13630–4
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): 361–72
Ruiz i Altaba A, Palma V, Dahmane N. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 2002 Jan; 3 (1): 24–33
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): 6063–71
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): 70–3
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): 3438–43
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): 876–81
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): 851–6
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): 567–81
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): 1169–78
Lindsell CE, Shawber CJ, Boulter J, et al. Jagged: a mammalian ligand that activates Notchl. Cell 1995 Mar 24; 80 (6): 909–17
Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 2002; 25: 471–90
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): 557–68
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): 823–6
Frisen J, Lendahl U. Oh no, Notch again! Bioessays 2001 Jan; 23 (1): 3–7
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): 7445–52
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): 269–71
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): 7794–800
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): 115–24
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): R605–15
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): 563–77
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): 204–17
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): 652–9
Nicolas M, Wolfer A, Raj K, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet 2003 Mar; 33 (3): 416–21
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): 1098–103
List of target genes of Wnt/β-catenin signaling. Updated 2007 Aug [online]. Available from URL: http://www.stanford.edu/R~rnusse/pathways/targets.html [Accessed 2007 Aug 6]
Kelly OG, Pinson KI, Skarnes WC. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 2004 Jun; 131 (12): 2803–15
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): 567–78
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): 15853–8
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): 35081–7
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): 2381–8
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): 241–50
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): 251–63
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): 1709–13
He XC, Zhang J, Li L. Cellular and molecular regulation of hematopoietic and intestinal stem cell behavior. Ann NY Acad Sci 2005 May; 1049: 28–38
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): 184–7
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): 409–14
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): 356–62
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): 1943–7
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): 5221–5
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): 3935–40
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): 237–43
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): 4240–5
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): 11960–5
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): 4713–20
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): 540–5
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): 250–9
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): 117–27
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): 1284–92
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): 1480–5
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): 518–22
Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006 May 25; 441 (7092): 475–82
He XC, Yin T, Grindley JC, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 2007 Feb; 39 (2): 189–98
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): 1432–7
Molofsky AV, Pardal R, Morrison SJ. Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 2004 Dec; 16 (6): 700–7
Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 2003 Feb; 13 (1): 77–83
Scadden DTC, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000 Mar 10; 287 (5459): 1804–8
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): 6–17
Soussi T. The p53 pathway and human cancer. Br J Surg 2005 Nov; 92 (11): 1331–2
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): 145–55
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): 165–71
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): 631–42
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): 643–55
Meletis K, Wirta V, Hede SM, et al. p53 suppresses the self-renewal of adult neural stem cells. Development 2006 Jan; 133 (2): 363–9
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): 302–5
Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004 Nov; 114 (9): 1299–307
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): 203–11
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): 421–6
Molofsky AV, Slutsky SG, Joseph NM, et al. Increasing pl6INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006 Sep 28; 443 (7110): 448–52
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): 488–501
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): 656–60
Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007 Feb 8; 445 (7128): 661–5
Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004 Jul; 51 (1): 1–28
Spira AI, Carducci MA. Differentiation therapy. Curr Opin Pharmacol 2003 Aug; 3 (4): 338–43
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): 157–65
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): 1021–8
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): 3241–9
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): 1172–83
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): 1356–63
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): 4019–24
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): 2743–8
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): 1022–31
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): 6071–4
Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002 Aug 30; 297 (5586): 1559–61
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): 12561–6
Watkins DN, Berman DM, Baylin SB. Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell Cycle 2003 May–Jun; 2 (3): 196–8
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): 846–51
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): 223–30
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): 979–86
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): 215–21
Pollard M, Luckert PH. Indomethacin treatment of rats with dimethylhydrazine-induced intestinal tumors. Cancer Treat Rep 1980; 64 (12): 1323–7
Meyskens FL. Chemoprevention of FAP with sulindac [letter]. Curr Oncol Rep 2002 Nov; 4 (6): 463
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): 335–45
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): 147–54
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): 91–102
Shah NM, Groves AK, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 1996 May 3; 85 (3): 331–43
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): 761–5
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): 249–58
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): 4181–7
Vassilev LT. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 2004 Apr; 3 (4): 419–21
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): 3432–5
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): 1239–46
Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006 Oct; 12 (10): 1167–74
Acknowledgments
We wish to thank Dr Christophe Ginestier for his helpful comments. This study was supported by grants from the National Institutes of Health (grants RO1-CA101860 and P30CA46592) and by the US Department of Defense. Dr Wicha has financial holdings and is a scientific adviser for OncoMed Pharmaceuticals.
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Korkaya, H., Wicha, M.S. Selective Targeting of Cancer Stem Cells. BioDrugs 21, 299–310 (2007). https://doi.org/10.2165/00063030-200721050-00002
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DOI: https://doi.org/10.2165/00063030-200721050-00002