Jennings M T, Pietenpol J A
Department of Neurology, Vanderbilt Cancer Center, Nashville, TN 37232-3375, USA.
J Neurooncol. 1998 Jan;36(2):123-40. doi: 10.1023/a:1005863419880.
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.
本综述探讨了转化生长因子β（TGFβ）在正常神经胶质细胞中作为生长抑制剂的调节作用，与在胶质母细胞瘤（GM）中作为进展因子的调节作用之间明显矛盾的转变。在体外，TGFβ作为任何级别的近二倍体胶质瘤的自分泌生长抑制剂发挥作用。相比之下，超二倍体多形性胶质母细胞瘤（HD-GM）培养物在TGFβ的作用下增殖，这是由血小板衍生生长因子B链（PDGF-BB）的诱导介导的。TGFβ与恶性转化的致病关联的主要假说是基于对其生长抑制作用的抗性获得。然而，HD-GM与TGFβ抑制的GM培养物之间在TGFβ受体（TβR）表达（或缺失）方面缺乏明显相关性，这表明存在受TGFβ影响的内在相反调节机制。转化机制可能通过介导TGFβ生长抑制作用的假定肿瘤抑制基因（TSG）的缺失来解释，或者通过HD-GM中活跃致癌途径的增强来解释。胶质瘤相关TSG（如TP53和RB）内的突变频率表明，TGFβ抑制信号通路的缺陷在向HD-GM进展以及TGFβ向有丝分裂原的转化中可能具有类似作用。可能解释TGFβ抑制作用丧失的其他失活位点包括II型TβR的失活突变/缺失、受体后信号转导的改变或调节pRB磷酸化的细胞周期蛋白/细胞周期蛋白依赖性激酶系统的改变。神经胶质TSG的缺失或失活以及随之而来的抑制失败似乎使TGFβ的其他组成效应（如c-sis的诱导）在功能上占主导地位。从机制上讲，TGFβ从自分泌抑制剂向有丝分裂原的转化通过在调节PDGF-A和c-sis方面的定性和定量差异，赋予超二倍体亚群达尔文优势，从而促进“克隆优势”，同时旁分泌抑制竞争性的近二倍体成分。
