TRANSFORMING GROWTH-FACTOR-BETA AS A POTENTIAL TUMOR PROGRESSION FACTOR AMONG HYPERDIPLOID GLIOBLASTOMA CULTURES - EVIDENCE FOR THE ROLE OFPLATELET-DERIVED GROWTH-FACTOR

Among early-passage, near-diploid gliomas in vitro, transforming growt h factor type beta (TGF beta) has been previously shown to be an autoc rine growth inhibitor. In contrast, hyperdiploid (greater than or equa l to 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) culture s were autocrinely stimulated by the TGF beta. The mecha nism of this 'conversion' from autocrine inhibitor to mitogen is not understood; pr evious studies have suggested that platelet-derived growth factor (PDG F) might be modulated by TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA, - BB, as well as the PDGF receptor alpha and beta subunits (alpha/beta PPDGFR) between biopsies of the HD-GM and near-di ploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry d id not explain the discrepancy in their regulatory responses. Flow cyt ometry demonstrated that TGF beta's mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures, while the diploid cells were inhibited. Among the HD-GM, TGF beta 1 i nduced the RNA of PDGF-A, c-sis and TGF beta 1. The amount of PDGF-AA secreted following TGF beta treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BE, -AB , alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF b eta's induction of DNA synthesis among the HD-GM cell lines, indicatin g that PDGF served as the principal mediator of TGF beta's growth stim ulatory effect. By comparison, TGF beta induced only the RNA of PDGF-A and TGF beta 1 among the near-diploid GM; c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to T GF beta 1 was insufficient to prevent TGF beta's arrest of the near-di ploid cultures in G(1) phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGF beta' s modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cells might achieve 'clonal dominance'. We hypoth esize that TGF beta may serve as an autocrine promoter of GM progressi on by providing a selective advantage to the hyperdiploid subpopulatio n through the loss of a tumor suppressor gene which mediates TGF beta' s inhibitory effect.