Abstract
There is now compelling evidence that gliomas harbor a small population of cells, termed glioma-initiating cells (GICs), characterized by their ability to undergo self-renewal and initiate tumorigenesis. The development of therapeutic strategies targeted toward GIC signaling may improve the treatment of malignant gliomas. The characterization of GICs provides a clue to elucidating histological heterogeneity and treatment failure. The role of the stem cell marker CD133 in the initiation and progression of brain tumors is still uncertain. Here, we review some of the signaling mechanisms involved in GIC biology, such as phosphatase and tensin homolog (PTEN), sonic hedgehog, Notch, and WNT signaling pathways, maternal embryonic leucine-zipper kinase (MELK), BMI1, and Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling. In addition, we discuss the role of microRNAs in GICs by focusing on microRNA-21 regulation by type I interferon.
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References
Polyak K, Shipitsin M, Campbell-Marrotta L et al (2009) Breast tumor heterogeneity: causes and consequences. Breast Cancer Res 11(Suppl 1):S18
Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996
Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273
Mani SA, Guo W, Liao MJ et al (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715
Reya T, Morrison SJ, Clarke MF et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111
Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea––a paradigm shift. Cancer Res 66:1883–1890 (discussion 95–96)
Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401
Lee J, Son MJ, Woolard K et al (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13:69–80
Penuelas S, Anido J, Prieto-Sanchez RM et al (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15:315–327
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710
Dahlstrand J, Collins VP, Lendahl U (1992) Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res 52:5334–5341
Ignatova TN, Kukekov VG, Laywell ED et al (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206
Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
Eramo A, Ricci-Vitiani L, Zeuner A et al (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13:1238–1241
Kang MK, Kang SK (2007) Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Dev 16:837–847
Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67
Salmaggi A, Boiardi A, Gelati M et al (2006) Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 54:850–860
Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760
Zheng X, Shen G, Yang X et al (2007) Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res 67:3691–3697
Beier D, Hau P, Proescholdt M et al (2007) CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67:4010–4015
Sakariassen PO, Prestegarden L, Wang J et al (2006) Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci USA 103:16466–16471
Wang J, Sakariassen PO, Tsinkalovsky O et al (2008) CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122:761–768
Yao Y, Wang X, Jin K et al (2008) B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subset of brain tumor stem-like cells. J Neurooncol 89:121–129
Chen R, Nishimura MC, Bumbaca SM et al (2010) A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17:362–375
Kaloshi G, Mokhtari K, Carpentier C et al (2007) FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status. J Neurooncol 84:245–248
Liang Y, Bollen AW, Aldape KD et al (2006) Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma. BMC Cancer 6:97
Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390
Groszer M, Erickson R, Scripture-Adams DD et al (2001) Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294:2186–2189
Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22:103–114
Wetmore C (2003) Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. Curr Opin Genet Dev 13:34–42
Henrique D, Hirsinger E, Adam J et al (1997) Maintenance of neuroepithelial progenitor cells by Delta-Notch signalling in the embryonic chick retina. Curr Biol 7:661–670
Fan X, Matsui W, Khaki L et al (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66:7445–7452
Willert K, Brown JD, Danenberg E et al (2003) WNT proteins are lipid-modified and can act as stem cell growth factors. Nature 423:448–452
Reya T, Duncan AW, Ailles L et al (2003) A role for WNT signaling in self-renewal of haematopoietic stem cells. Nature 423:409–414
Nakano I, Kornblum HI (2006) Brain tumor stem cells. Pediatr Res 59:54R–58R
Park IK, Qian D, Kiel M et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–305
Lessard J, Sauvageau G (2003) Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423:255–260
Zheng H, Ying H, Yan H et al (2008) p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455:1129–1133
Bleau AM, Hambardzumyan D, Ozawa T et al (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4:226–235
Gregorian C, Nakashima J, Le Belle J et al (2009) Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis. J Neurosci 29:1874–1886
Kwon CH, Zhao D, Chen J et al (2008) Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res 68:3286–3294
Xiao A, Wu H, Pandolfi PP et al (2002) Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 1:157–168
Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045
Huang H, Mahler-Araujo BM, Sankila A et al (2000) APC mutations in sporadic medulloblastomas. Am J Pathol 156:433–437
Dahmen RP, Koch A, Denkhaus D et al (2001) Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 61:7039–7043
Lee J, Platt KA, Censullo P et al (1997) Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124:2537–2552
Katayama M, Yoshida K, Ishimori H et al (2002) Patched and smoothened mRNA expression in human astrocytic tumors inversely correlates with histological malignancy. J Neurooncol 59:107–115
Clement V, Sanchez P, de Tribolet N et al (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17:165–172
Wang J, Wakeman TP, Lathia JD et al (2010) Notch promotes radioresistance of glioma stem cells. Stem Cells 28:17–28
Nakano I, Masterman-Smith M, Saigusa K et al (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res 86:48–60
Hemmati HD, Nakano I, Lazareff JA et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183
Abdouh M, Facchino S, Chatoo W et al (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29:8884–8896
Yuki K, Natsume A, Yokoyama H et al (2009) Induction of oligodendrogenesis in glioblastoma-initiating cells by IFN-mediated activation of STAT3 signaling. Cancer Lett 284:71–79
Esquela-Kerscher A, Slack FJ (2006) Oncomirs––microRNAs with a role in cancer. Nat Rev Cancer 6:259–269
Schickel R, Boyerinas B, Park SM et al (2008) MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 27:5959–5974
Silber J, Lim DA, Petritsch C et al (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14
Godlewski J, Newton HB, Chiocca EA et al (2010) MicroRNAs and glioblastoma; the stem cell connection. Cell Death Differ 17:221–228
Kefas B, Comeau L, Floyd DH et al (2009) The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J Neurosci 29:15161–15168
Ernst A, Campos B, Meier J et al (2010) De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures. Oncogene 29:3411–3422
Meng F, Henson R, Wehbe-Janek H et al (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658
Zhu S, Si ML, Wu H et al (2007) MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282:14328–14336
Chen Y, Liu W, Chao T et al (2008) MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G. Cancer Lett 272:197–205
Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65:6029–6033
Singh SK, Kagalwala MN, Parker-Thornburg J et al (2008) REST maintains self-renewal and pluripotency of embryonic stem cells. Nature 453:223–227
Karpala AJ, Doran TJ, Bean AG (2005) Immune responses to dsRNA: implications for gene silencing technologies. Immunol Cell Biol 83:211–216
Katze MG, He Y, Gale M Jr (2002) Viruses and interferon: a fight for supremacy. Nat Rev Immunol 2:675–687
Pedersen IM, Cheng G, Wieland S et al (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449:919–922
Borden EC, Sen GC, Uze G et al (2007) Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 6:975–990
Ohno M, Natsume A, Kondo Y et al (2009) The modulation of microRNAs by type I IFN through the activation of signal transducers and activators of transcription 3 in human glioma. Mol Cancer Res 7:2022–2030
Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902
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A. Natsume and S. Kinjo contributed equally to the preparation of this review article.
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Natsume, A., Kinjo, S., Yuki, K. et al. Glioma-initiating cells and molecular pathology: implications for therapy. Brain Tumor Pathol 28, 1–12 (2011). https://doi.org/10.1007/s10014-010-0011-3
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DOI: https://doi.org/10.1007/s10014-010-0011-3