TRANSFORMING GROWTH FACTORS IN NEOPLASTIC TRANSFORMATION

这些研究的总体目标是阐明 多肽生长因子在上皮性和非上皮性卵巢癌发生中的作用 间叶性肿瘤。这个实验室之前的研究已经 证明(1)转化生长因子-β(TGFβ)是一种 无处不在的生长调节分子；(2)特异性细胞膜受体 在多种细胞类型上均有表达；(3) 无论是促进生长还是抑制生长，获得的反应 在很大程度上取决于细胞类型；(4)某些化学转化 间充质细胞以增殖的方式产生和响应 以及(5)转化的角质形成细胞可能失去正常的 对转化生长因子β的抑制反应。拟议的研究旨在测试 假设转化生长因子β的产生和/或反应的变化 可能在肿瘤转化中发挥作用。转型可能会导致 从许多结缔组织中增强的刺激反应 上皮性肿瘤或某些组织抑制反应减弱 其他肿瘤。这些假说将得到检验，其机制 转化生长因子β促进某些细胞类型的生长和抑制其生长 其他类型的细胞将通过以下具体目标进行调查： (2)活性的转化生长因子β前体的性质和 激活的生理机制。这很可能是一个重要的 TGFbeta行动的调控步骤，因为大多数测试的细胞都产生这两种物质 转化生长因子β以非活性形式存在，并具有转化生长因子β膜受体。(2)A类 测定转化生长因子βmRNA含量是否随生长发育而变化 用小鼠转化生长因子β的cDNADNA探针检测转化状态。(3)A类 通过测定控制对转化生长因子β反应的基因 检测在静止状态下结构性表达的已知生长相关基因 化学转化的细胞相对于静止的未转化的细胞。我们 之前已经表明，化学转化的一个重大变化 细胞对转化生长因子β的反应性增强，这是一种 显然部分是通过c-myc基因的表达来调节的。(4)A类 转化生长因子β诱导的细胞基因表达的比较 TGFbeta试图理解一个纯因子 可作为一种细胞类型的生长刺激剂和一种细胞类型的生长抑制因子 又一个。(5)人对转化生长因子β抑制反应的比较 乳腺上皮细胞和相关的肿瘤转化细胞和 确定抑制反应丧失的机制。

The overall objective of these studies is to elucidate the role of polypeptide growth factors in the genesis of both epithelial and mesenchymal neoplasms. Previous studies from this laboratory have demonstrated that (1) transforming growth factor, type Beta (TGFBeta) is a ubiquitous growth regulatory molecule; (2) specific cell membrane receptor for TGFBeta are present on a wide variety of cell types; (3) TGFBeta can either be growth stimulatory or growth inhibitory wih the response obtained depending largely on cell type; (4) certain chemically transformed mesenchymal cells both produce and respond in a proliferative manner to TGFBeta; and (5) transformed keratinocytes may lose their normally inhibitory response to TGFBeta. The proposed studies are designed to test the hypothesis that alterations in production of and/or response to TGFBeta may play a role in neoplastic transformation. Transformation could result from either an increased stimulatory response in many connective tissue neoplasms or a decreased inhibitory response in epithelial and certain other neoplasms. These hypotheses will be tested and the mechanism of TGFBeta growth stimulation of certain cell types and growth inhibition of other cell types will be investigated through the following specific aims: (2) a determination of the nature of the active TGFBeta precursor and the physiological mechanism of activation. This is likely to be an important regulatory step in TGFBeta action since most cells tested both produce TGFBeta in an inactive form and have TGFBeta membrane receptors. (2) A determination of whether the TGFBeta mRNA content varies with growth or transformation state by using the cDNA probe for mouse TGFBeta. (3) A determination of the genes controlling responsiveness to TGFBeta by examining known growth related genes constitutively expressed in resting chemically transformed cells relative to resting nontransformed cells. We have previously shown that a major change in the chemically transformed cells is an increased responsiveness to TGFBeta, a function that is apparently modulated in part through expression of the c-myc gene. (4) A comparison of genes induced by TGFBeta in cells stimulated and inhibited by TGFBeta in an attempt to understand the mechanisms whereby a pure factor can act as a growth stimulator for one cell type and a growth inhibitor for another. (5) A comparison of the inhibitory response to TGFBeta in human mammary epithelial cells and related neoplastically transformed cells and a determination of the mechanism of loss of the inhibitory response.