Abstract
Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation and differentiation. Recently, several groups have described the existence of a cancer stem cell population in human brain tumors of different phenotypes from both children and adults. The finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by identification of cell surface markers that allow for isolation of distinct tumor cell populations that can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage markers, represent a minority fraction of the entire brain tumor cell population, and exclusively generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity. BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and brain tumorigenesis.
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References
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF . (2003). Proc. Natl. Acad. Sci. USA, 100, 3983–3988.
Altman J . (1963). Anat. Rec., 145, 573–591.
Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN and DePinho RA . (2002). Cancer Cell, 1, 269–277.
Bailey P and Cushing H . (1926). A Classification of Tumors in the Glioma Group. Lippincott: Philadelphia.
Blair A, Hogge DE, Ailles LE, Lansdorp PM and Sutherland HJ . (1997). Blood, 89, 3104–3112.
Bonnet D and Dick JE . (1997). Nat. Med., 3, 730–737.
Buzanska L, Spassky N, Belin MF, Giangrande A, Guillemot F, Klambt C, Labouesse M, Thomas JL, Domanska-Janik K and Zalc B . (2001). J. Neurosci. Res., 65, 17–23.
Copeland DD and Bigner DD . (1977). Acta Neuropathol. (Berl.), 38, 1–6.
Copeland DD, Vogel FS and Bigner DD . (1975). J. Neuropathol. Exp. Neurol., 34, 340–358.
Corbeil D, Roper K, Weigmann A and Huttner WB . (1998). Blood, 91, 2625–2626.
Dahlstrand J, Collins VP and Lendahl U . (1992). Cancer Res., 52, 5334–5341.
Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H and Ruiz i Altaba A . (2001). Development, 128, 5201–5212.
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM and Alvarez-Buylla A . (1999). Cell, 97, 703–716.
Fuchs E and Segre JA . (2000). Cell, 100, 143–155.
Gage FH . (2000). Science, 287, 1433–1438.
Gage FH . (2002). J. Neurosci., 22, 612–613.
Gilbertson RJ . (2004). Lancet Oncol., 5, 209–218.
Globus JH and Kuhlenbeck H . (1944). J. Neuropathol. Exp. Neurol., 3, 1–35.
Gross CG . (2000). Nat. Rev. Neurosci., 1, 67–73.
Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI . (2003). Proc. Natl. Acad. Sci. USA, 100, 15178–15183.
Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE and Fuller GN . (2000). Nat. Genet., 25, 55–57.
Holland EC, Hively WP, DePinho RA and Varmus HE . (1998). Genes Dev., 12, 3675–3685.
Hopewell JW and Wright EA . (1969). Cancer Res., 29, 1927–1931.
Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD and Steindler DA . (2002). Glia, 39, 193–206.
Kadin ME, Rubenstein LJ and Nelson JS . (1970). J. Neuropathol. Exp. Neurol., 29, 583–600.
Kilpatrick TJ and Bartlett PF . (1993). Neuron, 10, 255–265.
Koestner A, Swenberg JA and Wechsler W . (1971). Am. J. Pathol., 63, 37–50.
Kondo T, Setoguchi T and Taga T . (2004). Proc. Natl. Acad. Sci. USA, 101, 781–786.
Lendahl U, Zimmerman LB and McKay RD . (1990). Cell, 60, 585–595.
Lewis PD . (1968). Nature, 217, 974–975.
Lois C and Alvarez-Buylla A . (1993). Proc. Natl. Acad. Sci. USA, 90, 2074–2077.
Mackillop WJ, Blundell J and Steele P . (1985). Childs Nerv. Syst., 1, 163–168.
Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK and DePinho RA . (2001). Genes Dev., 15, 1311–1333.
Maris JM and Denny CT . (2002). Cancer Cell, 2, 447–450.
Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI and Jones RJ . (2004). Blood, 103, 2332–2336.
Morrison SJ, White PM, Zock C and Anderson DJ . (1999). Cell, 96, 737–749.
Pardal R, Clarke M and Morrison S . (2003). Nat. Rev. Cancer, 3, 895–902.
Pereira DS, Dorrell C, Ito CY, Gan OI, Murdoch B, Rao VN, Zou JP, Reddy ES and Dick JE . (1998). Proc. Natl. Acad. Sci. USA, 95, 8239–8244.
Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES and Golub TR . (2002). Nature, 415, 436–442.
Reya T, Morrison SJ, Clarke MF and Weissman IL . (2001). Nature, 414, 105–111.
Reynolds BA and Weiss S . (1992). Science, 255, 1707–1710.
Rubinstein LJ . (1972). J. Neuropathol. Exp. Neurol., 31, 7–26.
Ruiz i Altaba A, Sanchez P and Dahmane N . (2002). Nat. Rev. Cancer, 2, 361–372.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB . (2003). Cancer Res., 63, 5821–5828.
Smart I . (1961). J. Comp. Neurol., 116, 325–347.
Tamaki S, Eckert K, He D, Sutton R, Doshe M, Jain G, Tushinski R, Reitsma M, Harris B, Tsukamoto A, Gage F, Weissman I and Uchida N . (2002). J. Neurosci. Res., 69, 976–986.
Temple S . (2001). Nature, 414, 112–117.
Tohyama T, Lee VM, Rorke LB, Marvin M, McKay RD and Trojanowski JQ . (1992). Lab. Invest., 66, 303–313.
Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH and Weissman IL . (2000). Proc. Natl. Acad. Sci. USA, 97, 14720–14725.
Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN and Holland EC . (2002). Cancer Res., 62, 5551–5558.
Vick NA, Lin MJ and Bigner DD . (1977). Acta Neuropathol. (Berl.), 40, 63–71.
Wechsler-Reya R and Scott MP . (2001). Annu. Rev. Neurosci., 24, 385–428.
Weissman IL . (2000). Cell, 100, 157–168.
Zhu Y and Parada LF . (2002). Nat. Rev. Cancer, 2, 616–626.
Acknowledgements
Dr Dirks laboratory is supported by the National Cancer Institute of Canada, the Hospital for Sick Children Research Institute and the Arthur and Sonia Labatt Brain Tumor Research Center and from donations to his laboratory from the Jack Baker family and the Jessica Durigon family. Dr Singh's fellowship is supported by the Neurosurgery Research and Education Foundation with funds from the American Brain Tumor Association. We apologize to investigators of important research that was not cited in this review.
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Brain tumor cell lines also contain cancer stem cells. Study of a ‘side population’ of the C6 rat glioma cell line, based on the abilities of cells to exclude the fluorescent dye Hoechst 33342, demonstrates that this minority fraction of cells in this cell line exclusively have neural stem cell-like properties in vitro, and tumorigenic ability in vivo following transplantation into the peritoneal cavity of nude mice (Kondo et al., 2004).
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Singh, S., Clarke, I., Hide, T. et al. Cancer stem cells in nervous system tumors. Oncogene 23, 7267–7273 (2004). https://doi.org/10.1038/sj.onc.1207946
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DOI: https://doi.org/10.1038/sj.onc.1207946
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