PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

该计划的长期目标是识别多种分子 在人类前列腺癌的发病机制中相互作用的事件。 我们 获得了几种异常表达相关的证据 前列腺癌的基因。雄激素亚型的分子克隆- 诱导生长因子或 FGF8，在人类前列腺癌细胞中表达， 被分离和表征。 对他们的功能研究有 表明 FGF8 表达有助于生物行为 前列腺癌细胞。 在前列腺恶性上皮中我们发现 另外两个有趣的基因的过度表达：HSF1，热休克 因子和 L-plastin（一种肌动蛋白捆绑蛋白亚型）。 核 转录因子 HSF1 似乎主要位于 低风险（B 期）前列腺癌细胞的细胞质，而其 高风险（C 期）前列腺核中的分布增加 癌细胞。 L-plastin 表达的抑制导致抑制 前列腺癌细胞的运动和侵袭。 我们建议延长 这些研究旨在确定 FGF8 亚型和 FGF 受体家族成员在基质和上皮细胞中表达 前列腺细胞，以及这些相互作用在前列腺中的作用 癌症进展。 HSF1过表达的基础和潜力 将研究其亚细胞定位的新方面。 关于L-plastin，我们将专门检查前列腺癌是否 可以通过高效、组织抑制侵袭和转移 特异性反义L-塑蛋白基因表达。 扩展我们的小说 腺内和肿瘤内频繁发生的发现 前列腺肿瘤中 p53 突变的遗传异质性，我们还将 寻求确定 p53 突变是否能够拯救缺氧的前列腺 癌细胞或来自具有 p53 突变的焦点区域的细胞是否具有 更高的转移倾向。 这些研究综合起来， 应该会给前列腺癌的发病机制带来新的见解。 最终，对这些分子事件的理解将为我们提供 治疗和/或管理这种疾病的新方法 越来越常见的疾病。

The long-term goal of this program is to identify multiple molecular events that interplay in the pathogenesis of human prostate cancer. We obtained evidence for the association of abnormal expression of several genes in prostate cancer. Molecular clones of isoforms of androgen- induced growth factor or FGF8, expressed in human prostate cancer cells, were isolated and characterized. Functional studies with them have suggested that FGF8 expression contributes to biological behavior of prostate cancer cells. In the prostatic malignant epithelium we found overexpression of two other interesting genes: HSF1, a heat shock factor, and L-plastin, an actin-bundling protein isoform. The nuclear transcription factor HSF1 appears to be primarily localized in the cytoplasm of the low risk (stage B) prostate carcinoma cells, while its distribution is increased in the nucleus of high risk (stage C) prostate cancer cells. Inhibition of L-plastin expression results in suppression of motility and invasion of prostate cancer cells. We propose to extend these studies to determine the interactions between FGF8 isoforms and members of the FGF receptor family expressed in stromal and epithelial cells of the prostate, and the role of these interactions in prostate cancer progression. The basis of HSF1 overexpression and potential novel aspects of its subcellular localization will be investigated. Concerning L-plastin, we will specifically examine if prostate cancer invasion and metastasis can be inhibited by high efficiency, tissue specific antisense L-plastin gene expression. To extend our novel finding of the frequent occurrence of intraglandular and intratumor genetic heterogeneity of p53 mutations in prostate tumors, we will also seek to determine if p53 mutations arise to rescue hypoxic prostate cancer cells or whether cells from focal regions with p53 mutations have a higher propensity to metastasize. These studies, in combination, should lead to new insights into the pathogenesis of prostate cancer. Ultimately, an understanding of these molecular events will provide us with new approaches to the treatment and/or management of this increasingly common disease.