Yonsei Med J.  2010 Sep;51(5):633-640. 10.3349/ymj.2010.51.5.633.

Brain Tumor Stem Cells as Therapeutic Targets in Models of Glioma

• Laks DR
• Visnyei K
• Kornblum H

• KMID: 1071412
• DOI: http://doi.org/10.3349/ymj.2010.51.5.633

Abstract

At this time, brain tumor stem cells remain a controversial hypothesis while malignant brain tumors continue to present a dire prognosis of severe morbidity and mortality. Yet, brain tumor stem cells may represent an essential cellular target for glioma therapy as they are postulated to be the tumorigenic cells responsible for recurrence. Targeting oncogenic pathways that are essential to the survival and growth of brain tumor stem cells represents a promising area for developing therapeutics. However, due to the multiple oncogenic pathways involved in glioma, it is necessary to determine which pathways are the essential targets for therapy. Furthermore, research still needs to comprehend the morphogenic processes of cell populations involved in tumor formation. Here, we review research and discuss perspectives on models of glioma in order to delineate the current issues in defining brain tumor stem cells as therapeutic targets in models of glioma.

Keyword

Brain tumor stem cell; cancer stem cell; glioma; glioblastoma multiforme (GBM); neurosphere; PI3 kinase; Notch; Akt; Rapamycin

MeSH Terms

1-Phosphatidylinositol 3-Kinase/genetics/metabolism
Animals
Brain Neoplasms/genetics/*metabolism/*pathology/therapy
Glioma/genetics/*metabolism/*pathology/therapy
Humans
Neoplastic Stem Cells/*metabolism/*pathology
Receptors, Notch/genetics/metabolism
Signal Transduction/genetics/physiology

Figure

• 

  Fig. 1 Different tumor models of GBM. According to the cancer stem cell model (left panel), a subpopulation of cancer cells possesses the capacity of self-renewal, clonal sphere formation and in vivo tumor formation, as well as the capability to form progeny with a more restricted fate (darker colors). This forms a hierarchical lineage system where the primary therapeutic cell target is the CSC itself. The clonal evolution model (middle panel) exhibits no lineage hierarchy, as the multiple cell populations are the result of different genetic mutations (broken arrows). There is no cell hierarchy, because most of these cell subtypes self-renew and are capable of tumor formation, which makes them all targets of therapeutic interventions. In a complex system (right panel), both genetic and epigenetic changes might occur within a single tumor, resulting in a multifaceted cell system where several tumor-initiating cell types may coexist. While genetic mutations may produce new tumor cell populations (#3), epigenetic changes (#2) might enable cells to produce progeny with a more or less restricted fate and also to temporarily adopt different states characterized by therapy resistance and expression of different cell markers. Another important feature of a complex system is that the individual cell populations interact (red arrows, #4). While all potential tumor forming cells have to be targeted for successful therapy in this model, the interruption of the cell-cell and cell-niche interactions may also weaken the tumor system as a whole. GBM, glioblastoma multiforme; CSC, cancer stem cell.

Reference

1. Jukich PJ, McCarthy BJ, Surawicz TS, Freels S, Davis FG. Trends in incidence of primary brain tumors in the United States, 1985-1994. Neuro Oncol. 2001. 3:141–151.

2. Deorah S, Lynch CF, Sibenaller ZA, Ryken TC. Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001. Neurosurg Focus. 2006. 20:E1.

3. Deltour I, Johansen C, Auvinen A, Feychting M, Klaeboe L, Schüz J. Time trends in brain tumor incidence rates in Denmark, Finland, Norway, and Sweden, 1974-2003. J Natl Cancer Inst. 2009. 101:1721–1724.

4. Pirouzmand F, Sadanand V. The incidence trends of primary brain tumors in Saskatchewan from 1970 to 2001. Can J Neurol Sci. 2007. 34:181–186.

5. Smith MA, Freidlin B, Ries LA, Simon R. Trends in reported incidence of primary malignant brain tumors in children in the United States. J Natl Cancer Inst. 1998. 90:1269–1277.

6. Hess KR, Broglio KR, Bondy ML. Adult glioma incidence trends in the United States, 1977-2000. Cancer. 2004. 101:2293–2299.

7. Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol. 2006. 2:494–503.

8. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol. 2002. 4:278–299.

9. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin. 2007. 25:867–890.

10. Buckner JC, Brown PD, O'Neill BP, Meyer FB, Wetmore CJ, Uhm JH. Central nervous system tumors. Mayo Clin Proc. 2007. 82:1271–1286.

11. Miller CR, Perry A. Glioblastoma. Arch Pathol Lab Med. 2007. 131:397–406.

12. Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P. Grading of astrocytomas. A simple and reproducible method. Cancer. 1988. 62:2152–2165.

13. Burger PC, Kleihues P. Cytologic composition of the untreated glioblastoma with implications for evaluation of needle biopsies. Cancer. 1989. 63:2014–2023.

14. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005. 352:987–996.

15. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001. 414:105–111.

16. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003. 3:895–902.

17. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006. 355:1253–1261.

18. Nakano I, Kornblum HI. Brain tumor stem cells. Pediatr Res. 2006. 59:54R–58R.

19. Dahlstrand J, Collins VP, Lendahl U. Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res. 1992. 52:5334–5341.

20. Tohyama T, Lee VM, Rorke LB, Marvin M, McKay RD, Trojanowski JQ. Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab Invest. 1992. 66:303–313.

21. Wiese C, Rolletschek A, Kania G, Blyszczuk P, Tarasov KV, Tarasova Y, et al. Nestin expression--a property of multi-lineage progenitor cells? Cell Mol Life Sci. 2004. 61:2510–2522.

22. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005. 353:811–822.

23. Hadjipanayis CG, Van Meir EG. Brain cancer propagating cells: biology, genetics and targeted therapies. Trends Mol Med. 2009. 15:519–530.

24. Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia. 2002. 39:193–206.

25. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A. 2003. 100:15178–15183.

26. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003. 63:5821–5828.

27. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992. 255:1707–1710.

28. Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci. 1992. 12:4565–4574.

29. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004. 64:7011–7021.

30. Singh SK, Clarke ID, Hide T, Dirks PB. Cancer stem cells in nervous system tumors. Oncogene. 2004. 23:7267–7273.

31. Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, et al. Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells. 2009. 27:980–987.

32. Pallini R, Ricci-Vitiani L, Banna GL, Signore M, Lombardi D, Todaro M, et al. Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res. 2008. 14:8205–8212.

33. Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, Kurnit DM, et al. Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res. 2001. 61:6885–6891.

34. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006. 9:157–173.

35. Günther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R, et al. Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene. 2008. 27:2897–2909.

36. Tso CL, Freije WA, Day A, Chen Z, Merriman B, Perlina A, et al. Distinct transcription profiles of primary and secondary glioblastoma subgroups. Cancer Res. 2006. 66:159–167.

37. Nakano I, Masterman-Smith M, Saigusa K, Paucar AA, Horvath S, Shoemaker L, et al. Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res. 2008. 86:48–60.

38. Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, et al. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl Acad Sci U S A. 2006. In press.

39. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science. 2002. 298:601–604.

40. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001. 411:349–354.

41. Wechsler-Reya R, Scott MP. The developmental biology of brain tumors. Annu Rev Neurosci. 2001. 24:385–428.

42. Li Z, Wang H, Eyler CE, Hjelmeland AB, Rich JN. Turning cancer stem cells inside out: an exploration of glioma stem cell signaling pathways. J Biol Chem. 2009. 284:16705–16709.

43. Nakano I, Paucar AA, Bajpai R, Dougherty JD, Zewail A, Kelly TK, et al. Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J Cell Biol. 2005. 170:413–427.

44. Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, et al. Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res. 2003. 63:2742–2746.

45. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002. 2:489–501.

46. Wang G, Kang C, Pu P. Increased expression of Akt2 and activity of PI3K and cell proliferation with the ascending of tumor grade of human gliomas. Clin Neurol Neurosurg. 2010. 112:324–327.

47. Maira SM, Stauffer F, Schnell C, Garcia-Echeverria C. PI3K inhibitors for cancer treatment: where do we stand? Biochem Soc Trans. 2009. 37:265–272.

48. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994. 369:756–758.

49. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004. 4:335–348.

50. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A. 1994. 91:12574–12578.

51. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 1994. 78:35–43.

52. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006. 66:1500–1508.

53. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008. 5:e8.

54. Hosoi H, Dilling MB, Liu LN, Danks MK, Shikata T, Sekulic A, et al. Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol. 1998. 54:815–824.

55. Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol. 2010. 22:169–176.

56. Carracedo A, Baselga J, Pandolfi PP. Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors. Cell Cycle. 2008. 7:3805–3809.

57. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009. 284:8023–8032.

58. Thoreen CC, Sabatini DM. Rapamycin inhibits mTORC1, but not completely. Autophagy. 2009. 5:725–726.

59. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci. 2002. 25:471–490.

60. Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, 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. 65:2353–2363.

61. Solecki DJ, Liu XL, Tomoda T, Fang Y, Hatten ME. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron. 2001. 31:557–568.

62. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006. 442:823–826.

63. Pierfelice TJ, Schreck KC, Eberhart CG, Gaiano N. Notch, neural stem cells, and brain tumors. Cold Spring Harb Symp Quant Biol. 2008. 73:367–375.

64. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007. 318:287–290.

65. Mischel PS, Cloughesy TF. Targeted molecular therapy of GBM. Brain Pathol. 2003. 13:52–61.

66. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006. 66:4715–4724.

67. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood. 2007. 110:278–286.

68. Perumalsamy LR, Nagala M, Banerjee P, Sarin A. A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells. Cell Death Differ. 2009. 16:879–889.

69. Ma J, Meng Y, Kwiatkowski DJ, Chen X, Peng H, Sun Q, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 2010. 120:103–114.

70. Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, et al. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways. J Cell Biochem. 2010. 109:726–736.

71. Kitano H. A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov. 2007. 6:202–210.

72. Hambardzumyan D, Becher OJ, Holland EC. Cancer stem cells and survival pathways. Cell Cycle. 2008. 7:1371–1378.

73. Johannessen TC, Bjerkvig R, Tysnes BB. DNA repair and cancer stem-like cells--potential partners in glioma drug resistance? Cancer Treat Rev. 2008. 34:558–567.

74. Lu C, Shervington A. Chemoresistance in gliomas. Mol Cell Biochem. 2008. 312:71–80.

75. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005. 5:275–284.

76. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A. 2004. 101:14228–14233.

77. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976. 194:23–28.

78. Miller DG. On the nature of susceptibility to cancer. The presidential address. Cancer. 1980. 46:1307–1318.

79. Loeb LA. A mutator phenotype in cancer. Cancer Res. 2001. 61:3230–3239.

80. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008. 322:1377–1380.

81. Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009. 461:809–813.

82. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009. 138:822–829.

83. Shapiro JR, Yung WK, Shapiro WR. Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cancer Res. 1981. 41:2349–2359.

84. Yung WK, Shapiro JR, Shapiro WR. Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture. Cancer Res. 1982. 42:992–998.

85. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006. 444:761–765.

86. Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc Natl Acad Sci U S A. 2001. 98:13361–13366.

87. Westra JW, Peterson SE, Yung YC, Mutoh T, Barral S, Chun J. Aneuploid mosaicism in the developing and adult cerebellar cortex. J Comp Neurol. 2008. 507:1944–1951.

88. Sareen D, McMillan E, Ebert AD, Shelley BC, Johnson JA, Meisner LF, et al. Chromosome 7 and 19 trisomy in cultured human neural progenitor cells. PLoS One. 2009. 4:e7630.

89. Schwab ED, Pienta KJ. Cancer as a complex adaptive system. Med Hypotheses. 1996. 47:235–241.

90. Kitano H. Cancer as a robust system: implications for anticancer therapy. Nat Rev Cancer. 2004. 4:227–235.

91. Heppner GH. Tumor heterogeneity. Cancer Res. 1984. 44:2259–2265.

92. Axelrod R, Axelrod DE, Pienta KJ. Evolution of cooperation among tumor cells. Proc Natl Acad Sci U S A. 2006. 103:13474–13479.

93. Grizzi F, Chiriva-Internati M. The complexity of anatomical systems. Theor Biol Med Model. 2005. 2:26.

94. Grizzi F, Chiriva-Internati M. Cancer: looking for simplicity and finding complexity. Cancer Cell Int. 2006. 6:4.

95. Ashby W. Requisite variety and its implications for the control of complex systems. Cybernetica. 1958. 1:83–89.

96. Gilbertson RJ, Rich JN. Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer. 2007. 7:733–736.

97. Hoelzinger DB, Demuth T, Berens ME. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst. 2007. 99:1583–1593.

98. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007. 11:69–82.

99. Wu M, Pastor-Pareja JC, Xu T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature. 2010. 463:545–548.