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和 间叶肿瘤 该实验室以前的研究表明， 证明（1）转化生长因子β（TGF β）是一种 普遍存在的生长调节分子;（2）特异性细胞膜受体 TGF β存在于多种细胞类型上;（3）TGF β可以 或者是生长刺激性的或者是生长抑制性的 主要取决于细胞类型;（4）某些化学转化的 间充质细胞以增殖的方式产生并响应 TGF β;和（5）转化的角质形成细胞可能失去其正常的 对TGF β的抑制反应。 拟议的研究旨在测试 TGF β的产生和/或对TGF β的反应的改变 可能在肿瘤转化中起作用。 转化可能导致 要么是由于许多结缔组织的刺激反应增强 肿瘤或上皮细胞和某些 其他肿瘤。 这些假设将得到检验， 某些细胞类型的TGF β生长刺激和 将通过以下具体目标研究其他细胞类型： (2)确定活性TGF β前体的性质， 激活的生理机制。 这可能是一个重要的 调节步骤，因为大多数细胞测试都产生 TGF β处于非活性形式，并具有TGF β膜受体。 (2)一 确定TGF β mRNA含量是否随生长而变化， 通过使用小鼠TGF β的cDNA探针检测转化状态。 (3)一 确定控制对TGF β反应性的基因， 检查已知的生长相关基因在静息状态下组成型表达， 化学转化的细胞相对于静止的非转化细胞。 我们 先前已经表明，化学转化的主要变化 细胞对TGF β的反应性增加，这种功能是 显然部分通过c-myc基因的表达调节。 (4)一 比较TGF β刺激和抑制的细胞中TGF β诱导的基因 TGF β试图了解一个纯因子 可以作为一种细胞类型的生长刺激剂， 另 (5)人对TGF β抑制反应的比较 乳腺上皮细胞和相关的肿瘤转化细胞以及 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.