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This review begins with the description of the nervous cytogenesis, proliferation of primitive cells, migration and differentiation with antigen expression and regulation through factors. Emphasis is given to neural stem cells, progenitors and to radial glia as belonging to early stages of gliogenesis. Experimental production of brain tumors in the rat by transplacental administration of ethylnitrosourea and systemic administration of methylnitrosourea effective through neural stem cells and progenitors is briefly described as a preamble to the recent conception of gliomas as originating from stem cells or brain tumor stem cells (BTSCs). The nature and origin of BTSCs, their molecular regulation and their recognition in vivo are discussed. In the growth of tumors, the role of nestin, migration of neural stem cells toward the tumor from the subventricular zone or from the tumor to the brain and the migration from bone marrow of mesenchymal stem cells for angiogenesis of the tumors are considered. Special mention is made of the relationship between glio-vascular niches in the subventricular zone and the neo-niches around the tumors with their importance in the tumor growth as points of joint between cytogenesis and angiogenesis. Finally, besides the importance of hypoxia, cell traffic in the brain adjacent to tumor is emphasized in relation to the growth of gliomas.

The mammalian target of rapamycin (mTOR) controls cell growth through protein synthesis regulation. It can be activated by protein kinase B (AKT) or through ribosomal S6 kinase (S6K1). In malignant glioma, mTOR inhibitors have antiproliferative and proapoptotic effects and mTOR has been suggested as a target of therapies, thus it is worthwhile to verify its relations with the phosphatidylinositol-3-kinase (PI3)/AKT cascade, proliferation and apoptosis in human gliomas.In a series of 64 gliomas, including high- and low-grade tumors, AKT, mTOR, S6, caspase-3, poly(ADP-ribose) polymerase 1 (PARP1) and cleaved PARP1, Ki-67/MIB.1 and beclin 1 were studied by molecular biology techniques, quantitative immunohistochemistry and Western blotting.mTOR (phospho-mTOR), S6 (phospho-S6), AKT (phospho-AKT) levels and Ki-67/MIB.1 labelling index (LI) increased with increasing grade of malignancy. Epithelial growth factor receptor (EGFR) amplification correlated with EGFRwt and EGFRvIII immunohistochemistry, and with AKT expression; the latter correlated with mTOR expression, whereas S6 expression correlated with Ki-67/MIB.1 LI. Within the category of glioblastoma, S6 but not mTOR correlated with proliferation. mTOR did not show correlation with apoptosis, whereas it was inversely correlated with beclin 1, in line with the observation that autophagy is not activated in many malignancies.The relationship of S6 with the proliferation markers emphasizes the importance of the position of S6K1 downstream AKT in the PI3/AKT pathway.

Survivin is expressed in proliferating tissues and in tumors. It is a member of the inhibitory apoptosis protein (IAP) family known to regulate mitosis and to inhibit apoptosis. It has therefore been regarded as a target for therapies. In malignant gliomas it increases with malignancy, even though in glioblastomas it does not seem to correlate with outcome.Survivin was immunohistochemically studied in 39 selected viable glioblastoma areas belonging to 20 cases which were assayed for apoptosis, using a TUNEL assay, caspase-3, poly(ADP-ribose)polymerase 1 (PARP-1), Bid (BH3-interacting domain death agonist) and with the proliferation index Ki-67/MIB-1 and mitotic index (MI).A positive linear correlation was found between the survivin labelling index (LI) and the Ki-67/MIB-1 LI and MI. No inverse correlation was found with apoptosis.This double behavior can be attributed to mechanisms mediating survivin activity, either as a mitosis regulator and apoptosis inhibitor, and should be taken into account in therapeutic strategies using survivin.

The direct and indirect regulation, as well as the mechanisms of apoptosis in the nervous tissue and their implications in the treatment and prognosis of brain tumors are reviewed.