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The role of transforming growth factor beta in glioma progression
1Department of Neurology, Vanderbilt Cancer Center, Nashville, TN 37232-3375, USA.
Abstract:
This review examines the apparently paradoxical conversion of transforming growth factor beta's (TGFbeta) regulatory role as a growth inhibitor among normal glial cells to that of a progression factor among glioblastomas (GM). In vitro, TGFbeta 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 TGFbeta, which is mediated by induction of platelet-derived growth factor B chain (PDGF-BB). The dominant hypothesis of TGFbeta'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 TGFbeta receptor (TbetaR) expression (or loss) between the HD-GM and the TGFbeta-inhibited GM cultures suggests the existence of intrinsically opposed regulatory mechanisms influenced by TGFbeta. The mechanism of conversion might be explained either by the loss of a putative tumor suppressor gene (TSG) which mediates TGFbeta'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 TGFbeta's inhibitory signaling pathway may have analogous effects in the progression to HD-GM, and TGFbeta's conversion to a mitogen. Alternative sites of inactivation which might explain the loss of TGFbeta's inhibitory effect include inactivating mutation/loss of the TbetaR 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 TGFbeta's other constitutive effects, such as induction of c-sis, to become functionally dominant. Mechanistically, TGFbeta'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.
Insights
Transforming growth factor beta (TGFbeta) inhibits normal glial cells but promotes glioblastoma growth by inducing platelet-derived growth factor B chain (PDGF-BB). This paradoxical role shift in glioblastoma may involve tumor suppressor gene inactivation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Transforming growth factor beta (TGFbeta) typically inhibits growth in normal glial cells.
- Glioblastomas (GM) exhibit a paradoxical response to TGFbeta, with some subtypes proliferating.
- Understanding TGFbeta's dual role is crucial for glioblastoma progression insights.
Purpose of the Study:
- To review the mechanisms behind TGFbeta's conversion from a growth inhibitor to a progression factor in glioblastomas.
- To explore the molecular basis for differential TGFbeta signaling in normal glial cells versus glioblastoma subtypes.
- To investigate the role of tumor suppressor genes and oncogenic pathways in this TGFbeta-mediated conversion.
Main Methods:
- Review of in vitro studies on TGFbeta's effects on normal glial cells and various glioma cultures (near-diploid vs. hyperdiploid glioblastoma multiforme - HD-GM).
- Analysis of signaling pathways, including platelet-derived growth factor B chain (PDGF-BB) induction in HD-GM.
- Examination of potential genetic alterations in TGFbeta receptors (TbetaR), tumor suppressor genes (TSG) like TP53 and RB, and downstream effectors (e.g., pRB, cyclin/CDK system).
Main Results:
- TGFbeta inhibits near-diploid gliomas but stimulates proliferation in hyperdiploid glioblastoma multiforme (HD-GM) cultures.
- TGFbeta-induced proliferation in HD-GM is mediated by platelet-derived growth factor B chain (PDGF-BB) upregulation.
- Lack of correlation between TbetaR expression and TGFbeta response suggests complex regulatory mechanisms beyond receptor levels.
Conclusions:
- TGFbeta's conversion to a mitogenic factor in HD-GM may result from loss of tumor suppressor gene function or activation of oncogenic pathways.
- Defects in TGFbeta's inhibitory signaling pathway, potentially through TSG inactivation (e.g., TP53, RB) or TbetaR mutations, facilitate glioblastoma progression.
- TGFbeta promotes 'clonal dominance' in HD-GM by modulating PDGF-A and c-sis, conferring a survival advantage over less malignant cells.