Hostname: page-component-586b7cd67f-g8jcs Total loading time: 0 Render date: 2024-11-28T14:26:55.879Z Has data issue: false hasContentIssue false
  • English
  • Français

Stem Cells in Brain Tumour Development and Therapy- Two-Sides of the Same Coin

Published online by Cambridge University Press:  02 December 2014

Cathy Lee ,
Sandra E. Dunn  and
Stephen Yip
Cathy Lee
Affiliation:
Department of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, University of British Columbia
Sandra E. Dunn*
Affiliation:
Department of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, University of British Columbia
Stephen Yip
Affiliation:
Department of Pathology & Laboratory Medicine, Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, BC, Canada
*
Department of Pediatrics, University of British Columbia, Room 3082, 950 West 28th Avenue, Vancouver, BC, V6L 1G4, Canada.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Primary brain tumours are difficult to manage clinically due to their abilities to invade adjacent tissue and infiltrate distant neuropil. These contribute to challenges in surgical management and also limit the effectiveness of radiotherapy. Despite initial responses to chemotherapy, most tumours become chemo-resistant, leading to relapse. Recent identification and isolation of brain cancer stem cells (BCSCs) have broadened our understanding of the molecular pathogenesis and potential Achilles' heel of brain tumours. BCSCs are thought to drive and propagate the tumour and therefore present an important target for further investigations. This review explores the history of the discovery of BCSCs and the evolving concept of “cancer stem cells” in neuro-oncology. We attempt to present a balanced view on the subject and also to update the readers on the molecular biology of BCSCs. Lastly, we outline the potential strategies to target BCSCs which will translate into specific and effective therapies for brain tumours.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 39 , Issue 2 , March 2012 , pp. 145 - 156
Copyright
Copyright © The Canadian Journal of Neurological 2012

References

1Wen, PY, Kesari, S.Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.Google Scholar
2Schiff, D, Brown, PD, Giannini, C.Outcome in adult low-grade glioma: the impact of prognostic factors and treatment. Neurology. 2007;69:1366–73.CrossRefGoogle ScholarPubMed
3Bourne, TD, Schiff, D.Update on molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol. 2010;6: 695–701.Google Scholar
4Yang, I, Aghi, MK.New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol. 2009;6:648–57.Google Scholar
5Altman, J, Das, GD.Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124:319–35.Google Scholar
6Altman, J.Proliferation and migration of undifferentiated precursor cells in the rat during postnatal gliogenesis. Exp Neurol. 1966; 16:263–78.Google Scholar
7Dacey, ML, Wallace, RB.Postnatal neurogenesis in the feline cerebellum: a structural-functional investigation. Acta Neurobiol Exp (Wars). 1974;34:253–63.Google ScholarPubMed
8Goldman, SA, Nottebohm, F.Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci USA. 1983;80:2390–4.CrossRefGoogle Scholar
9Alvarez-Buylla, A, Theelen, M, Nottebohm, F.Birth of projection neurons in the higher vocal center of the canary forebrain before, during, and after song learning. Proc Natl Acad Sci USA. 1988; 85:8722–6.Google Scholar
10Reynolds, BA, Weiss, S.Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255:1707–10.Google Scholar
11Roy, NS, Wang, S, Jiang, L, et al.In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med. 2000;6:271–7.Google Scholar
12Palmer, TD, Schwartz, PH, Taupin, P, Kaspar, B, Stein, SA, Gage, FH.Cell culture. Progenitor cells from human brain after death. Nature. 2001;411:42–3.Google Scholar
13Vescovi, AL, Galli, R, Reynolds, BA.Brain tumour stem cells. Nat Rev Cancer. 2006;6:425–36.Google Scholar
14Al-Hajj, M, Becker, MW, Wicha, M, Weissman, I, Clarke, MF.Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14:43–7.Google Scholar
15Reya, T, Morrison, SJ, Clarke, MF, Weissman, IL.Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.Google Scholar
16Lapidot, T, Sirard, C, Vormoor, J, et al.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.CrossRefGoogle ScholarPubMed
17Bonnet, D, Dick, JE.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.Google Scholar
18Hope, 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;5:738–43.Google Scholar
19Al-Hajj, M, Wicha, MS, Benito-Hernandez, A, Morrison, SJ, Clarke, MF.Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.Google Scholar
20Fang, D, Nguyen, TK, Leishear, K, et al.A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 2005;65:9328–37.Google Scholar
21Li, C, Heidt, DG, Dalerba, P, et al.Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.Google Scholar
22O’Brien, CA, Pollett, A, Gallinger, S, Dick, JE.A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.Google Scholar
23Patrawala, L, Calhoun, T, Schneider-Broussard, R, et al.Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25:1696–708.CrossRefGoogle ScholarPubMed
24Singh, SK, Clarke, ID, Terasaki, M, et al.Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.Google Scholar
25Singh, SK, Hawkins, C, Clarke, ID, et al.Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.Google Scholar
26Hemmati, HD, Nakano, I, Lazareff, JA, et al.Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA. 2003;100:15178–83.Google Scholar
27Galli, R, Binda, E, Orfanelli, U, et al.Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.Google Scholar
28Ignatova, TN, Kukekov, VG, Laywell, ED, Suslov, ON, Vrionis, FD, Steindler, DA.Human cortical glial tumors contain neural stemlike cells expressing astroglial and neuronal markers in vitro. Glia. 2002;39:193–206.Google Scholar
29Gritti, A, Parati, EA, Cova, L, et al.Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci. 1996;16:1091–100.Google Scholar
30Reynolds, BA, Rietze, RL.Neural stem cells and neurospheres-re-evaluating the relationship. Nat Methods. 2005;2:333–6.Google Scholar
31Shackleton, M.Normal stem cells and cancer stem cells: similar and different. Semin Cancer Biol. 2010;20:85–92.Google Scholar
32Holland, EC, Hively, WP, DePinho, RA, Varmus, HE.A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce gliomalike lesions in mice. Genes Dev. 1998;12:3675–85.Google Scholar
33Holland, EC, Celestino, J, Dai, C, Schaefer, L, Sawaya, RE, Fuller, GN.Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. 2000;25: 55–7.CrossRefGoogle ScholarPubMed
34Bachoo, RM, Maher, EA, Ligon, KL, et al.Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1:269–77.Google Scholar
35Huse, JT, Holland, EC.Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010;10:319–31.CrossRefGoogle ScholarPubMed
36Assanah, M, Lochhead, R, Ogden, A, Bruce, J, Goldman, J, Canoll, P.Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci. 2006;26:6781–90.Google Scholar
37G. B. Bone marrow-derived cells in GBM neovascularization. CNS Cancer: Models, Markers, Prognostic Factors, Targets and Therapeutic Approaches. 1st ed: New York: Humana Press (Springer); 2009.Google Scholar
38Van Meir, EG, Hadjipanayis, CG, Norden, AD, Shu, HK, Wen, PY, Olson, JJ.Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin. 2010;60: 166–93.Google Scholar
39Das, S, Srikanth, M, Kessler, JA.Cancer stem cells and glioma. Nat Clin Pract Neurol. 2008;4:427–35.Google Scholar
40Calabrese, C, Poppleton, H, Kocak, M, et al.A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11:69–82.Google Scholar
41Bao, S, Wu, Q, Sathornsumetee, S, et al.Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66:7843–8.Google Scholar
42Oka, N, Soeda, A, Inagaki, A, et al.VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells. Biochem Biophys Res Commun. 2007;360:553–9.Google Scholar
43Paez-Ribes, M, Allen, E, Hudock, J, et al.Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.Google Scholar
44Tuettenberg, J, Grobholz, R, Seiz, M, et al.Recurrence pattern in glioblastoma multiforme patients treated with anti-angiogenic chemotherapy. J Cancer Res Clin Oncol. 2009;135:1239–44.Google Scholar
45Laywell, ED, Kukekov, VG, Suslov, O, Zheng, T, Steindler, DA.Production and analysis of neurospheres from acutely dissociated and postmortem CNS specimens. Methods Mol Biol. 2002;198:15–27.Google Scholar
46Marshall, GP, 2nd, Reynolds, BA, Laywell, ED.Using the neurosphere assay to quantify neural stem cells in vivo. Curr Pharm Biotechnol. 2007;8:141–5.Google Scholar
47Liu, G, Yuan, X, Zeng, Z, et al.Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67.Google Scholar
48Bao, S, Wu, Q, McLendon, RE, et al.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.Google Scholar
49Lottaz, C, Beier, D, Meyer, K, et al.Transcriptional profiles of CD133+ and CD133- glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res. 2010;70: 2030–40.Google Scholar
50Beier, D, Hau, P, Proescholdt, M, et al.CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67: 4010–15.Google Scholar
51Joo, KM, Kim, SY, Jin, X, et al.Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest. 2008;88:808–15.CrossRefGoogle ScholarPubMed
52Wang, J, Sakariassen, PO, Tsinkalovsky, O, et al.CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122:761–8.CrossRefGoogle ScholarPubMed
53Pallini, R, Ricci-Vitiani, L, Banna, GL, et al.Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14:8205–12.Google Scholar
54Zhang, M, Song, T, Yang, L, et al.Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res. 2008;27:85.Google Scholar
55Skubitz, KM, Snook, RW, 2nd. Monoclonal antibodies that recognize lacto-N-fucopentaose III (CD15) react with the adhesion-promoting glycoprotein family (LFA-1/HMac-1/gp 150,95) and CR1 on human neutrophils. J Immunol. 1987;139:1631–9.Google Scholar
56Allendoerfer, KL, Magnani, JL, Patterson, PH.FORSE-1, an antibody that labels regionally restricted subpopulations of progenitor cells in the embryonic central nervous system, recognizes the Le(x) carbohydrate on a proteoglycan and two glycolipid antigens. Mol Cell Neurosci. 1995;6:381–95.Google Scholar
57Capela, A, Temple, S.LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron. 2002;35: 865–75.Google Scholar
58Capela, A, Temple, S.LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1. Dev Biol. 2006;291:300–13.Google Scholar
59Fox, N, Damjanov, I, Knowles, BB, Solter, D.Immunohistochemical localization of the mouse stage-specific embryonic antigen 1 in human tissues and tumors. Cancer Res. 1983;43:669–78.Google Scholar
60McCarthy, NC, Simpson, JR, Coghill, G, Kerr, MA.Expression in normal adult, fetal, and neoplastic tissues of a carbohydrate differentiation antigen recognised by antigranulocyte mouse monoclonal antibodies. J Clin Pathol. 1985;38:521–9.Google Scholar
61Son, MJ, Woolard, K, Nam, DH, Lee, J, Fine, HA.SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell. 2009;4:440–52.Google Scholar
62Ward, RJ, Lee, L, Graham, K, et al.Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma. Cancer Res. 2009;69:4682–90.Google Scholar
63Read, TA, Fogarty, MP, Markant, SL, et al.Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell. 2009;15:135–47.Google Scholar
64Chaudhary, PM, Roninson, IB.Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991;66:85–94.Google Scholar
65Dean, M.ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14:3–9.Google Scholar
66Hu, C, Li, H, Li, J, et al.Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling. Carcinogenesis. 2008;29:2289–97.Google Scholar
67Moitra, K, Lou, H, Dean, M.Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther. 2011;89:491–502.Google Scholar
68Hu, L, McArthur, C, Jaffe, RB.Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant. Br J Cancer. 2010;102:1276–83.Google Scholar
69Kim, M, Turnquist, H, Jackson, J, et al.The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res. 2002;8:22–8.Google Scholar
70Scharenberg, CW, Harkey, MA, Torok-Storb, B.The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood. 2002;99:507–12.Google Scholar
71Ho, MM, Ng, AV, Lam, S, Hung, JY.Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007;67:4827–33.Google Scholar
72Szotek, PP, Pieretti-Vanmarcke, R, Masiakos, PT, et al.Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA. 2006;103:11154–9.Google Scholar
73Hirschmann-Jax, C, Foster, AE, Wulf, GG, Goodell, MA, Brenner, MK.A distinct “side population” of cells in human tumor cells: implications for tumor biology and therapy. Cell Cycle. 2005;4: 203–5.Google Scholar
74Hirschmann-Jax, C, Foster, AE, Wulf, GG, et al.A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 2004;101:14228–33.Google Scholar
75Alvi, AJ, Clayton, H, Joshi, C, et al.Functional and molecular characterisation of mammary side population cells. Breast Cancer Res. 2003;5:R1–8.Google Scholar
76Shen, G, Shen, F, Shi, Z, et al.Identification of cancer stem-like cells in the C6 glioma cell line and the limitation of current identification methods. In Vitro Cell Dev Biol Anim. 2008;44: 280–9.Google Scholar
77Dean, M, Fojo, T, Bates, S.Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84.Google Scholar
78Storms, RW, Trujillo, AP, Springer, JB, et al.Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci USA. 1999;96: 9118–23.Google Scholar
79Corti, S, Locatelli, F, Papadimitriou, D, et al.Identification of a primitive brain-derived neural stem cell population based on aldehyde dehydrogenase activity. Stem Cells. 2006;24:975–85.CrossRefGoogle ScholarPubMed
80Fallon, P, Gentry, T, Balber, AE, et al.Mobilized peripheral blood SSCloALDHbr cells have the phenotypic and functional properties of primitive haematopoietic cells and their number correlates with engraftment following autologous transplantation. Br J Haematol. 2003;122:99–108.Google Scholar
81Hess, DA, Wirthlin, L, Craft, TP, et al.Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood. 2006; 107:2162–9.CrossRefGoogle ScholarPubMed
82Christ, O, Lucke, K, Imren, S, et al.Improved purification of hematopoietic stem cells based on their elevated aldehyde dehydrogenase activity. Haematologic. 2007;92:1165–72.Google Scholar
83Jiang, F, Qiu, Q, Khanna, A, et al.Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res. 2009;7:330–8.Google Scholar
84Liang, D, Shi, Y.Aldehyde dehydrogenase-1 is a specific marker for stem cells in human lung adenocarcinoma. Med Oncol. 2011. Apr 12 [Epub ahead of print]Google Scholar
85Charafe-Jauffret, E, Ginestier, C, Iovino, F, et al.Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009; 69:1302–13.Google Scholar
86Chu, P, Clanton, DJ, Snipas, TS, et al.Characterization of a subpopulation of colon cancer cells with stem cell-like properties. Int J Cancer. 2009;124:1312–21.Google Scholar
87Ma, S, Chan, KW, Lee, TK, et al.Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res. 2008;6:1146–53.Google Scholar
88Quemener, V, Moulinoux, JP, Martin, C, et al.Aldehyde dehydrogenase activity in xenografted human brain tumor in nude mice. Preliminary results in human glioma biopsies. J Neurooncol. 1990;9:115–23.Google ScholarPubMed
89Rasper, M, Schafer, A, Piontek, G, et al.Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro Oncol. 2010;12:1024–33.CrossRefGoogle ScholarPubMed
90Chen, YC, Chen, YW, Hsu, HS, et al.Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun. 2009;385:307–13.Google Scholar
91Su, Y, Qiu, Q, Zhang, X, et al.Aldehyde dehydrogenase 1 A1-positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer. Cancer Epidemiol Biomarkers Prev. 2010;19:327–37.Google Scholar
92Sun, S, Wang, Z.ALDH high adenoid cystic carcinoma cells display cancer stem cell properties and are responsible for mediating metastasis. Biochem Biophys Res Commun. 2010;396:843–8.Google Scholar
93Charafe-Jauffret, E, Ginestier, C, Iovino, F, et al.Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res. 2010;16:45–55.Google Scholar
94Marcato, P, Dean, CA, Pan, D, et al.Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells. 2010;Jan;29(1):32–45. doi: 10.1002/stem.563.Google Scholar
95Ran, D, Schubert, M, Pietsch, L, et al.Aldehyde dehydrogenase activity among primary leukemia cells is associated with stem cell features and correlates with adverse clinical outcomes. Exp Hematol. 2009;37:1423–34.Google Scholar
96Nalwoga, H, Arnes, JB, Wabinga, H, Akslen, LA.Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer. Br J Cancer. 2010;102:369–75.Google Scholar
97Li, T, Su, Y, Mei, Y, et al.ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients’ outcome. Lab Invest. 2010;90:234–44.Google Scholar
98Yoshioka, T, Umekita, Y, Ohi, Y, et al.Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study. Histopathology. 2011;58:608–16.Google Scholar
99Clement, V, Marino, D, Cudalbu, C, et al.Marker-independent identification of glioma-initiating cells. Nat Methods. 2010;7: 224–8.Google Scholar
100Visvader, JE, Lindeman, GJ.Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.Google Scholar
101Dalerba, P, Dylla, SJ, Park, IK, et al.Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 2007;104:10158–63.Google Scholar
102Shackleton, M, Quintana, E, Fearon, ER, Morrison, SJ.Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009; 138:822–9.Google Scholar
103Feuring-Buske, M, Gerhard, B, Cashman, J, Humphries, RK, Eaves, CJ, Hogge, DE.Improved engraftment of human acute myeloid leukemia progenitor cells in beta 2-microglobulin-deficient NOD/SCID mice and in NOD/SCID mice transgenic for human growth factors. Leukemia. 2003;17:760–3.Google Scholar
104Barabe, F, Kennedy, JA, Hope, KJ, Dick, JE.Modeling the initiation and progression of human acute leukemia in mice. Science. 2007;316:600–4.Google Scholar
105Quintana, E, Shackleton, M, Sabel, MS, Fullen, DR, Johnson, TM, Morrison, SJ.Efficient tumour formation by single human melanoma cells. Nature. 2008;456:593–8.Google Scholar
106Gupta, PB, Chaffer, CL, Weinberg, RA.Cancer stem cells: mirage or reality? Nat Med. 2009;15:1010–2.Google Scholar
107Hatton, BA, Villavicencio, EH, Tsuchiya, KD, et al.The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res. 2008;68:1768–76.Google Scholar
108Zhou, BB, Zhang, H, Damelin, M, Geles, KG, Grindley, JC, Dirks, PB.Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8:806–23.Google Scholar
109Fan, X, Mikolaenko, I, Elhassan, I, et al.Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res. 2004;64:7787–93.Google Scholar
110Hallahan, 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;64:7794–800.Google Scholar
111Purow, BW, Haque, RM, Noel, MW, et al.Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005;65:2353–63.Google Scholar
112Dakubo, GD, Mazerolle, CJ, Wallace, VA.Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice. J Neurooncol. 2006;79:221–7.Google Scholar
113Fan, X, Matsui, W, Khaki, L, et al.Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006;66:7445–52.Google Scholar
114Clark, PA, Treisman, DM, Ebben, J, Kuo, JS.Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn. 2007;236:3297–308.Google Scholar
115Weiner, HL, Bakst, R, Hurlbert, MS, et al.Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1. Cancer Res. 2002;62:6385–9.Google Scholar
116Berman, DM, Karhadkar, SS, Hallahan, AR, et al.Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002;297:1559–61.Google Scholar
117Dahmane, N, Sanchez, P, Gitton, Y, et al.The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development. 2001;128:5201–12.Google Scholar
118del Amo, FF, Gendron-Maguire, M, Swiatek, PJ, Jenkins, NA, Copeland, NG, Gridley, T.Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch. Genomics. 1993;15:259–64.Google Scholar
119Weinmaster, G, Roberts, VJ, Lemke, G.Notch2: a second mammalian Notch gene. Development. 1992;116:931–41.Google Scholar
120Lardelli, M, Lendahl, U.Motch A and motch B-two mouse Notch homologues coexpressed in a wide variety of tissues. Exp Cell Res. 1993;204:364–72.Google Scholar
121Lardelli, M, Dahlstrand, J, Lendahl, U.The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev. 1994;46:123–36.Google Scholar
122Uyttendaele, H, Marazzi, G, Wu, G, Yan, Q, Sassoon, D, Kitajewski, J.Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development. 1996;122: 2251–9.Google Scholar
123Bettenhausen, B, Hrabe de Angelis, M, Simon, D, Guenet, JL, Gossler, A.Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development. 1995;121:2407–18.Google Scholar
124Dunwoodie, SL, Henrique, D, Harrison, SM, Beddington, RS.Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development. 1997;124: 3065–76.Google Scholar
125Shutter, JR, Scully, S, Fan, W, et al.Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 2000;14:1313–18.Google Scholar
126Lindsell, CE, Shawber, CJ, Boulter, J, Weinmaster, G.Jagged: a mammalian ligand that activates Notch1. Cell. 1995;80:909–17.Google Scholar
127Shawber, C, Boulter, J, Lindsell, CE, Weinmaster, G.Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev Biol. 1996;180:370–6.Google Scholar
128Radtke, F, Raj, K.The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003;3:756–67.Google Scholar
129Androutsellis-Theotokis, A, Leker, RR, Soldner, F, et al.Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442:823–6.Google Scholar
130Hu, YY, Zheng, MH, Cheng, G, et al.Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells. BMC Cancer. 2011;11:82.Google Scholar
131Shih, AH, Holland, EC.Notch signaling enhances nestin expression in gliomas. Neoplasia. 2006;8:1072–82.Google Scholar
132Fan, X, Khaki, L, Zhu, TS, et al.NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells. 2010;28:5–16.Google Scholar
133Wang, J, Wang, C, Meng, Q, et al.siRNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth. Mol Biol Rep. 2011 Jun 12. [Epub ahead of print]Google Scholar
134Schreck, KC, Taylor, P, Marchionni, L, et al.The Notch target Hes1 directly modulates Gli1 expression and Hedgehog signaling: a potential mechanism of therapeutic resistance. Clin Cancer Res. 2010;16:6060–70.Google Scholar
135Duman-Scheel, M, Weng, L, Xin, S, Du, W.Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002;417:299–304.Google Scholar
136Mill, P, Mo, R, Fu, H, et al.Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev. 2003;17:282–94.Google Scholar
137Pasca di Magliano, M, Hebrok, M.Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3:903–11.Google Scholar
138Kenney, AM, Rowitch, DH.Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol. 2000;20:9055–67.Google Scholar
139Xu, Q, Yuan, X, Liu, G, Black, KL, Yu, JS.Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells. 2008;26:3018–26.Google Scholar
140Rao, G, Pedone, CA, Del Valle, L, Reiss, K, Holland, EC, Fults, DW.Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene. 2004;23: 6156–62.Google Scholar
141Pietsch, T, Waha, A, Koch, A, et al.Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997;57:2085–8.Google Scholar
142Raffel, C, Jenkins, RB, Frederick, L, et al.Sporadic medullo-blastomas contain PTCH mutations. Cancer Res. 1997;57:842–5.Google Scholar
143Reifenberger, J, Wolter, M, Weber, RG, et al.Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998;58:1798–803.Google Scholar
144Taylor, MD, Liu, L, Raffel, C, et al.Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31:306–10.Google Scholar
145Thompson, MC, Fuller, C, Hogg, TL, et al.Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol. 2006;24:1924–31.Google Scholar
146Kool, M, Koster, J, Bunt, J, et al.Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One. 2008;3:e3088.Google Scholar
147Beachy, PA, Karhadkar, SS, Berman, DM.Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324–31.Google Scholar
148Tabs, S, Avci, O.Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur J Dermatol. 2004;14:96–102.Google ScholarPubMed
149Michael, LE, Westerman, BA, Ermilov, AN, et al.Bmi 1 is required for Hedgehog pathway-driven medulloblastoma expansion. Neoplasia. 2008;10:1343–9.Google Scholar
150Leung, C, Lingbeek, M, Shakhova, O, et al.Bmi 1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature. 2004;428:337–41.Google Scholar
151Jacobs, JJ, Kieboom, K, Marino, S, DePinho, RA, van Lohuizen, M.The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999;397:164–8.Google Scholar
152Jacobs, JJ, Scheijen, B, Voncken, JW, Kieboom, K, Berns, A, van Lohuizen, M.Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999;13:2678–90.Google Scholar
153Wang, H, Wang, L, Erdjument-Bromage, H, et al.Role of histone H2A ubiquitination in Polycomb silencing. Nature. 2004;431: 873–8.Google Scholar
154Dellino, GI, Schwartz, YB, Farkas, G, McCabe, D, Elgin, SC, Pirrotta, V.Polycomb silencing blocks transcription initiation. Mol Cell. 2004;13:887–93.Google Scholar
155Francis, NJ, Kingston, RE.Mechanisms of transcriptional memory. Nat Rev Mol Cell Biol. 2001;2:409–21.Google Scholar
156Wang, L, Brown, JL, Cao, R, Zhang, Y, Kassis, JA, Jones, RS.Hierarchical recruitment of polycomb group silencing complexes. Mol Cell. 2004;14:637–46.Google Scholar
157Cao, R, Tsukada, Y, Zhang, Y.Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005;20: 845–54.Google Scholar
158Bracken, AP, Helin, K.Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer. 2009;9: 773–84.Google Scholar
159Lie, DC, Colamarino, SA, Song, HJ, et al.Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–5.Google Scholar
160Morris, DC, Zhang, ZG, Wang, Y, et al.Wnt expression in the adult rat subventricular zone after stroke. Neurosci Lett. 2007;418: 170–4.Google Scholar
161Wang, YZ, Yamagami, T, Gan, Q, et al.Canonical Wnt signaling promotes the proliferation and neurogenesis of peripheral olfactory stem cells during postnatal development and adult regeneration. J Cell Sci. 2011;124:1553–63.Google Scholar
162Zhang, L, Yang, X, Yang, S, Zhang, J.The Wnt/beta-catenin signaling pathway in the adult neurogenesis. Eur J Neurosci. 2011;33:1–8.Google Scholar
163Wharton, KA Jr. Runnin’ with the Dvl: proteins that associate with Dsh/Dvl and their significance to Wnt signal transduction. Dev Biol. 2003;253:1–17.Google Scholar
164Logan, CY, Nusse, R.The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.Google Scholar
165Gibson, P, Tong, Y, Robinson, G, et al.Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010;468:1095–9.Google Scholar
166Ellison, DW, Onilude, OE, Lindsey, JC, et al.beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol. 2005;23:7951–7.Google Scholar
167Rogers, HA, Miller, S, Lowe, J, Brundler, MA, Coyle, B, Grundy, RG.An investigation of WNT pathway activation and association with survival in central nervous system primitive neuroectodermal tumours (CNS PNET). Br J Cancer. 2009;100: 1292–302.Google Scholar
168Baeza, N, Masuoka, J, Kleihues, P, Ohgaki, H.AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene. 2003; 22:632–6.Google Scholar
169Huang, H, Mahler-Araujo, BM, Sankila, A, et al.APC mutations in sporadic medulloblastomas. Am J Pathol. 2000;156:433–7.CrossRefGoogle ScholarPubMed
170Ellison, DW, Dalton, J, Kocak, M, et al.Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121: 381–96.Google Scholar
171Ellison, DW, Kocak, M, Dalton, J, et al.Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol. 2011;29:1400–7.Google Scholar
172Koch, A, Waha, A, Tonn, JC, et al.Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer. 2001;93:445–9.Google Scholar
173Dahmen, RP, Koch, A, Denkhaus, D, et al.Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 2001;61:7039–43.Google Scholar
174Sareddy, GR, Panigrahi, M, Challa, S, Mahadevan, A, Babu, PP.Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int. 2009;55:307–17.Google Scholar
175Baryawno, N, Sveinbjornsson, B, Eksborg, S, Chen, CS, Kogner, P, Johnsen, JI.Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res. 2010; 70:266–76.Google Scholar
176Shou, J, Ali-Osman, F, Multani, AS, Pathak, S, Fedi, P, Srivenugopal, KS.Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene. 2002;21:878–89.Google Scholar
177Zheng, H, Ying, H, Yan, H, et al.p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455:1129–33.Google Scholar
178Wang, J, Wang, H, Li, Z, et al.c-Myc is required for maintenance of glioma cancer stem cells. PLoS One. 2008;3:e3769.Google Scholar
179Taipale, J, Chen, JK, Cooper, MK, et al.Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 2000;406:1005–9.Google Scholar
180Von Hoff, DD, LoRusso, PMRudin, CM, et al.Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361:1164–72.Google Scholar
181Amin, SH, Tibes, R, Kim, JE, Hybarger, CP.Hedgehog antagonist GDC-0449 is effective in the treatment of advanced basal cell carcinoma. Laryngoscope. 2010;120:2456–9.Google Scholar
182Morrison, R, Schleicher, SM, Sun, Y, et al.Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. J Oncol. 2011;2011:941876.Google Scholar
183Dijkgraaf, GJ, Alicke, B, Weinmann, L, et al.Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011; 71:435–44.Google Scholar
184Yauch, RL, Dijkgraaf, GJ, Alicke, B, et al.Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326:572–4.Google Scholar
185Buonamici, S, Williams, J, Morrissey, M, et al.Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2:51ra70.Google Scholar
186Yang, YP, Chang, YL, Huang, PI, et al.Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J Cell Physiol. 2011.Google Scholar
187Piccirillo, SG, Reynolds, BA, Zanetti, N, et al.Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444:761–5.Google Scholar
188Chirasani, SR, Sternjak, A, Wend, P, et al.Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain. 2010;133:1961–72.Google Scholar
189Lee, J, Son, MJ, Woolard, K, et al.Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13:69–80.Google Scholar
190Gao, Y, Fotovati, A, Lee, C, et al.Inhibition of Y-box binding protein-1 slows the growth of glioblastoma multiforme and sensitizes to temozolomide independent O6-methylguanine-DNA methyl-transferase. Mol Cancer Ther. 2009;8:3276–84.Google Scholar
191Fotovati, A, Abu-Ali, S, Wang, PS, et al.YB-1 bridges neural stem cells and brain-tumor initiating cells via its roles in differentiation and cell growth. Cancer Res. 2011 Aug 15;71 (16):5569–78. Epub 2011 Jul 5.Google Scholar
192Wakimoto, H, Kesari, S, Farrell, CJ, et al.Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res. 2009;69:3472–81.Google Scholar
193Zhu, G, Su, W, Jin, G, et al.Glioma stem cells targeted by oncolytic virus carrying endostatin-angiostatin fusion gene and the expression of its exogenous gene in vitro. Brain Res. 2011;1390: 59–69.Google Scholar
194Hambardzumyan, D, Becher, OJ, Rosenblum, MK, Pandolfi, PP, Manova-Todorova, K, Holland, EC.PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008;22:436–48.Google Scholar
195Yu, L, Baxter, PA, Zhao, X, et al.A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models. Neuro Oncol. 2011;13:14–27.Google Scholar