ROLE OF GROWTH FACTORS IN HUMAN PROSTATE CARCINOMA

这项提案的总体目标是确定S的角色 特定的生长调节通路在人前列腺发病中的作用 癌症。部分生长因子基因和原癌基因的表达 在自然疾病期间，将通过手术切除来评估进展情况 取自病人的样本。与一个或多个相关的基因表达 本课程将研究人类前列腺癌的病理生物学方面。 进一步在一个具有良好特征的人前列腺肿瘤实验模型中 裸鼠移植瘤的生长和转移。以下内容的表达 生长因子或生长因子受体基因将从以下方面进行检测 特定的RNA(通过Northern分析)、基因扩增(Southern 分析)和蛋白质产物(免疫组织化学和蛋白质分析)， 在可行的情况下：(1)转化生长因子α(TGF-α)及其 受体，(2)表皮生长因子受体(EGFR)，(3)c-erbB-2，a 编码修饰的EGF受体的基因，和(4)转化生长因子 β(转化生长因子-β1)。免疫组织化学染色与 将使用适当的抗体和Western blotting(1)来关联RNA 蛋白质产品表达水平和(2)允许识别 合成目标蛋白质的细胞类型。相关表达式 通过分析这些基因的作用(S)，这些基因将与功能相关 这些基因产物与肿瘤的生长和/或转移有关 人前列腺癌PC-3和DU145裸鼠移植瘤的研究 这将伴随着(1)特定基因表达的测量 现有的PC-3和DU145变种和(2)PC-3变种的选择 表现出这些基因的高或低表达，随后 在裸鼠身上的评价。在可能的情况下，确认推定 这些基因的功能参与将通过基因 通过适当的转基因修饰表型突变体 基因(S)。这些研究将有助于确定这些人(S)的角色 自然进程中的生长因子和生长因子受体基因 人类前列腺癌。同样重要的是，这些实验将 允许对这些表达之间的关系进行实验评估 这种常见人类肿瘤的基因和病理生物学表型。

The overall objective of this proposal is to determine the role(s) of specific growth regulatory pathways in the pathogenesis of human prostatic cancer. Expression of selected growth factor genes and protooncogenes during natural disease progression will be evaluated in surgically-excised specimens from patients. Gene expression which correlates with one or more aspects of the pathobiology of human prostate cancer will be examined further in a well characterized experimental model of human prostatic tumor growth and metastasis in athymic nude mice. Expression of the following growth factors or growth factor receptor genes will be examined in terms of both specific RNA (via Northern analysis), gene amplification (Southern analysis), and protein product (immunohistochemistry and Western analysis), where feasible: (1) transforming growth factor alpha (TGF-alpha) and its receptor, (2) the epidermal growth factor receptor (EGFr), (3) c-erbB-2, a gene coding for a modified EGF receptor, and (4) transforming growth factor beta (TGF-beta1). A combination of immunohistochemical staining with the appropriate antibody and Western blotting will be used (1) to relate RNA levels to protein product expression and (2) to permit identification of the cell type synthesizing the protein of interest. Correlative expression of these genes will be related to function by analysis of the role(s) of these gene products in the growth and/or metastasis of variants of the human prostate carcinoma cell line PC-3 and DU145 in athymic nude mice. This will be accompanied by (1) measurement of specific gene expression in existing PC-3 and DU145 variants and (2) selection of PC-3 variants which exhibit high or low expression of these genes followed by subsequent evaluation in nude mice. Where possible, confirmation of putative functional involvement of these genes will be sought by genetic modification of phenotypic variants via transfection with the appropriate gene(s). These studies will permit identification of the role(s) of these growth factor and growth factor receptor genes in the natural progression of human prostatic cancer. Equally significant, these experiments will permit experimental evaluation of the relation between expression of these genes and the pathobiological phenotype of this common human tumor.