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Transforming growth factor b as a potential tumor progression factor among hyperdiploid glioblastoma cultures: Evidence for the role of platelet-derived growth factor

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Abstract

Among early-passage, near-diploid gliomas in vitro, transforming growth factor type β (TGFβ) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (≥ 57chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGFβ. The mechanism of this ‘conversion’ from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGFβ. The similar expression of TGFβ types 1—3, PDGF-AA, — BB, as well as the PDGF receptor α and β subunits (a/βPDGFR) between biopsies of the HD-GM and near-diploid, TGFβ-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flowcytometry demonstrated that TGFβ'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, TGFβ1 induced the RNA of PDGF-A, c-sis and TGFβ1. The amount of PDGF-AA secreted following TGFβ treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB,αPDGFR and/or βPDGFR subunits effectively neutralized TGFβ's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGFβ's growth stimulatory effect. By comparison, TGFβ induced only the RNA of PDGF-A and TGFβ1 among the near-diploid GM; c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGFβ1 was insufficient to prevent TGFβ's arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGFβ's modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cellsmight achieve ‘clonal dominance’. We hypothesize that TGFβ may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGFβ's inhibitory effect.

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Authors and Affiliations

  1. Departments of Neurology, USA

    Mark T. Jennings & Paul L. Moots

  2. Neurosurgery, USA

    Patricia A. Commers & Robert J. Maciunas

  3. Pediatrics, USA

    James A. Whitlock & Danko Martincic

  4. Vanderbilt School of Medicine, ZymoGenetics, Seattle, WA

    Charles E. Hart

  5. Wayne State University, USA

    Thomas M. Shehab

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Jennings, M.T., Hart, C.E., Commers, P.A. et al. Transforming growth factor b as a potential tumor progression factor among hyperdiploid glioblastoma cultures: Evidence for the role of platelet-derived growth factor. J Neurooncol 31, 233–253 (1997). https://doi.org/10.1023/A:1005767616500

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