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The role of transforming growth factor Β in glioma progression

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Abstract

This review examines the apparently paradoxical conversion of transforming growth factor β's (TGFβ) regulatory role as a growth inhibitor among normal glial cells to that of a progression factor among glioblastomas (GM). In vitro, TGFβ functions as an autocrine growth inhibitor of near-diploid gliomas of any grade. In contrast, hyperdiploid glioblastoma multiforme (HD-GM) cultures proliferate in response to TGFβ, which is mediated by induction of platelet-derived growth factor B chain (PDGF-BB). The dominant hypothesis of TGFβ's pathogenetic association with malignant transformation has been predicated upon acquisition of resistance to its growth inhibitory effects. However, the lack of obvious correlation with TGFβ receptor (TβR) expression (or loss) between the HD-GM and the TGFβ-inhibited GM cultures suggests the existence of intrinsically opposed regulatory mechanisms influenced by TGFβ. The mechanism of conversion might be explained either by the loss of a putative tumor suppressor gene (TSG) which mediates TGFβ's inhibition of growth or by enhancement of an active oncogenic pathway among the HD-GM. The frequency of mutations within glioma-associated TSG, such as TP53 and RB, suggests that defects in TGFβ's inhibitory signaling pathway may have analogous effects in the progression to HD-GM, and TGFβ's conversion to a mitogen. Alternative sites of inactivation which might explain the loss of TGFβ's inhibitory effect include inactivating mutation/loss of the TβR type II, alterations in post-receptor signal transmission or the cyclin/cyclin dependent kinase system which regulates the phosphorylation of pRB. Loss or inactivation of a glial TSG with a consequent failure of inhibition appears to allow TGFβ's other constitutive effects, such as induction of c-sis, to become functionally dominant. Mechanistically, TGFβ's conversion from autocrine inhibitor to mitogen promotes 'clonal dominance' by conferring a Darwinian advantage to the hyperdiploid subpopulations through qualitative and quantitative differences in its modulation of PDGF-A and c-sis, with concomitant paracrine inhibition of competing, near-diploid elements. Abbreviations: transforming growth factor β (TGFβ) and receptor (TβR); retinoblastoma gene (RB) and protein (pRB); platelet-derived growth factor (PDGF) and receptor (PDGFR); epidermal growth factor (EGF) and receptor (EGFR); fibroblast growth factor (FGF); malignant glioma (MG), astrocytoma (AST), anaplastic astrocytoma (AAST), glioblastoma (GM); hyperdiploid glioblastoma (HD-GM); glioblastoma multiforme (GM); normal rat kidney (NRK); tumor suppressor gene (TSG); loss of heterozygosity (LOH); TP53 wild type (TP53wt); TP53 mutant (TP53m)

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  1. Departments of Neurology and Cell Biology, Vanderbilt Cancer Center, Nashville, TN, USA

    Mark T. Jennings & Jennifer A. Pietenpol

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Jennings, M.T., Pietenpol, J.A. The role of transforming growth factor Β in glioma progression. J Neurooncol 36, 123–140 (1998). https://doi.org/10.1023/A:1005863419880

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