The role of transforming growth factor β in glioma progression

This review examines the apparently paradoxical conversion of transforming growth factor beta's (TGF beta) regulatory role as a growth inhibitor among normal glial cells to that of a progression factor among glioblastomas (GM). In vitro, TGF beta 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 TGF beta, which is mediated by induction of platelet-derived growth factor B chain (PDGF-BB). The dominant hypothesis of TGF beta'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 TGF beta receptor (T beta R) expression (or loss) between the HD-GM and the TGF beta-inhibited GM cultures suggests the existence of intrinsically opposed regulatory mechanisms influenced by TGF beta. The mechanism of conversion might be explained either by the loss of a putative tumor suppressor gene (TSG) which mediates TGF beta'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 RE, suggests that defects in TGF beta's inhibitory signaling pathway may have analogous effects in the progression to HD-GM, and TGF beta's conversion to a mitogen. Alternative sites of inactivation which might explain the loss of TGF beta's inhibitory effect include inactivating mutation/loss of the T beta R 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 TGF beta's other constitutive effects, such as induction of c-sis, to become functionally dominant. Mechanistically, TGF beta'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.