Jennings M T, Hart C E, Commers P A, Whitlock J A, Martincic D, Maciunas R J, Moots P L, Shehab T M
Department of Neurology, Vanderbilt School of Medicine, USA.
J Neurooncol. 1997 Feb;31(3):233-54. doi: 10.1023/a:1005767616500.
Among early-passage, near-diploid gliomas in vitro, transforming growth factor type beta (TGF beta) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (> or = 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGF beta. 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 TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA; -BB, as well as the PDGF receptor alpha and beta subunits (a/beta PDGFR) between biopsies of the HD-GM and near-diploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flow cytometry 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 induced 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, -BB, -AB, alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF beta's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGF beta's growth stimulatory 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 TGF beta 1 was insufficient to prevent TGF beta's arrest of the near-diploid cultures in G1 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 hypothesize that TGF beta 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 TGF beta's inhibitory effect.
在体外培养的早期传代、近二倍体胶质瘤中，转化生长因子β（TGFβ）先前已被证明是一种自分泌生长抑制剂。相比之下，超二倍体（≥57条染色体/中期）多形性胶质母细胞瘤（HD - GM）培养物受到TGFβ的自分泌刺激。这种从自分泌抑制剂到有丝分裂原的“转变”机制尚不清楚；先前的研究表明血小板衍生生长因子（PDGF）可能受到TGFβ的调节。通过免疫组织化学检测，HD - GM活检组织与近二倍体、TGFβ抑制的胶质母细胞瘤（GM）之间，TGFβ1 - 3型、PDGF - AA、- BB以及PDGF受体α和β亚基（α/β PDGFR）的表达相似，这并不能解释它们在调节反应上的差异。流式细胞术表明，TGFβ的促有丝分裂作用对三种选定的HD - GM培养物中的两种非整倍体亚群具有选择性，而二倍体细胞则受到抑制。在HD - GM中，TGFβ1诱导了PDGF - A、c - sis和TGFβ1的RNA表达。TGFβ处理后分泌的PDGF - AA量足以刺激HD - GM培养物的增殖。针对PDGF - AA、- BB、- AB、α PDGFR和/或β PDGFR亚基的抗体有效地中和了HD - GM细胞系中TGFβ诱导的DNA合成，表明PDGF是TGFβ生长刺激作用的主要介质。相比之下，在近二倍体GM中，TGFβ仅诱导了PDGF - A和TGFβ1的RNA表达，c - sis根本不表达。然而，响应TGFβ1分泌的PDGF - A量不足以阻止TGFβ使近二倍体培养物停滞在G1期。因此，超二倍体的出现与TGFβ对PDGF - A和c - sis调节的质和量的差异有关，这为非整倍体胶质瘤细胞实现“克隆优势”提供了一种机制。我们假设TGFβ可能通过介导TGFβ抑制作用的肿瘤抑制基因的缺失，为超二倍体亚群提供选择性优势，从而作为GM进展的自分泌促进因子。
