Human cortical glial tumors contain neural stem‐like cells expressing astroglial and neuronal markers in vitro

GLIA - Tập 39 Số 3 - Trang 193-206 - 2002
Т Н Игнатова1,2, Valery G. Kukekov1,2, Eric D. Laywell1, Oleg Suslov1, Frank D. Vrionis3, Dennis A. Steindler1
1Departments of Neuroscience and Neurosurgery, McKnight Brain Institute and Shands Cancer Center, University of Florida, Gainesville, Florida
2T.N. Ignatova and V.G. Kukekov contributed equally to this study.
3NeuroOncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Tóm tắt

Abstract

Neural stem cells from neurogenic regions of mammalian CNS are clonogenic in an in vitro culture system exploiting serum and anchorage withdrawal in medium supplemented with methyl cellulose and the pleiotropic growth factors EGF, FGF2, and insulin. The aim of this study was to test whether cortical glial tumors contain stem‐like cells capable, under this culture system, of forming clones showing intraclonal heterogeneity in the expression of neural lineage‐specific proteins. The high frequencies of clone‐forming cells (about 0.1–10 × 10−3) in clinical tumor specimens with mutated p53, and in neurogenic regions of normal human CNS, suggest that the ability to form clones in this culture system is induced epigenetically. RT‐PCR analyses of populations of normal brain‐ and tumor‐derived sister clones revealed transcripts for nestin, neuron‐specific enolase, and glial fibrillary acidic protein (GFAP). However, the tumor‐derived clones were different from clones derived from neurogenic regions of normal brain in the expression of transcripts specific for genes associated with neural cell fate determination via the Notch‐signaling pathway (Delta and Jagged), and cell survival at G2 or mitotic phases (Survivin). Moreover, the individual glioma‐derived clones contain cells immunopositive separately for GFAP or neuronal β‐III tubulin, as well as single cells coexpressing both glial and neuronal markers. The data suggest that the latent critical stem cell characteristics can be epigenetically induced by growth conditions not only in cells from neurogenic regions of normal CNS but also in cells from cortical glial tumors. Moreover, tumor stem‐like cells with genetically defective responses to epigenetic stimuli may contribute to gliomagenesis and the developmental pathological heterogeneity of glial tumors. GLIA 39:193–206, 2002. © 2002 Wiley‐Liss, Inc.

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Tài liệu tham khảo

Adida C, 1998, Developmentally regulated expression of the novel cancer anti‐apoptosis gene Survivin in human and mouse differentiation, Am J Pathol, 152, 43

10.1038/nm0897-917

10.1093/carcin/19.9.1529

10.1152/jn.1998.79.5.2782

10.1023/A:1006331416283

10.1126/science.290.5497.1775

10.3171/jns.1995.82.1.0106

10.1007/BF01052659

Dahlstrand J, 1992, Expression of the class VI intermediate filament nestin in human central nervous system tumors, Cancer Res, 52, 5334

10.1016/S0092-8674(00)80783-7

Eaves CJ, 1995, Hematology, 122

10.1523/JNEUROSCI.21-15-05587.2001

10.1016/S0301-472X(00)00592-0

10.1073/pnas.88.12.5413

10.1038/79924

10.1038/sj.onc.1204630

10.1002/cne.903610205

10.1523/JNEUROSCI.19-09-03287.1999

10.1046/j.1460-9568.2000.00234.x

10.1038/43919

10.1016/S0304-3835(01)00499-2

10.1038/75596

10.1073/pnas.96.25.14482

10.1073/pnas.96.4.1457

10.1073/pnas.96.19.10711

10.1002/(SICI)1098-1136(199712)21:4<399::AID-GLIA7>3.0.CO;2-Z

10.1006/exnr.1999.7028

10.1002/glia.440150306

10.1038/81326

10.1006/exnr.1999.7029

10.1073/pnas.250471697

10.1016/0092-8674(90)90662-X

10.1038/25141

10.1006/nbdi.1995.0008

10.1006/mcne.1996.0040

Mahotka C, 1999, Survivin‐AEx3 and survivin‐2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties, Cancer Res, 59, 6098

10.1523/JNEUROSCI.11-11-03398.1991

10.1126/science.290.5497.1779

10.1002/(SICI)1097-4652(199912)181:3<393::AID-JCP3>3.0.CO;2-6

10.1016/S0092-8674(00)80583-8

10.1007/BF01052899

10.1023/A:1005898228116

10.1523/JNEUROSCI.20-22-08435.2000

10.1523/JNEUROSCI.19-19-08487.1999

10.1126/science.284.5417.1168

10.1126/science.1553558

10.1006/exnr.2000.7389

10.1016/S0166-2236(99)01416-2

10.1016/0304-3940(87)90721-X

10.1523/JNEUROSCI.21-18-07153.2001

10.1038/355846a0

10.3171/jns.1997.86.3.0525

10.1016/S0079-6123(08)62551-0

10.1016/S0165-0270(99)00177-6

10.1038/313223a0

10.1177/107385849500100305

10.1002/glia.1034

10.1006/dbio.1998.9192

10.1523/JNEUROSCI.20-10-03725.2000

10.1073/pnas.91.19.9009

Uhrbum L, 1998, Induction of brain tumors in mice using a recombinant platelet‐derived growth factor B‐chain retrovirus, Cancer Res, 58, 5275

10.1016/0896-6273(93)90124-A

10.1006/exnr.1998.6998

10.1016/S0959-437X(00)00097-6

10.1002/1097-4547(20000815)61:4<364::AID-JNR2>3.0.CO;2-C

Zhang T, 2001, Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer, Cancer Res, 62, 8664

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GLIA

Tập 39 Số 3

193-206

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