PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

该计划长期目标是识别多个分子 在人类前列腺癌发病机制中相互作用的事件。我们 获得了与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，在人前列腺癌细胞中表达， 并对其进行了分离和鉴定。对它们的功能研究 提示FGF8的表达与肿瘤的生物学行为有关。 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：热休克基因HSF1的过表达 因子，以及肌动蛋白捆绑蛋白亚型L-血浆蛋白。核电 转录因子HSF1似乎主要定位于 低危(B期)前列腺癌细胞的胞浆，而其 高危(C期)前列腺细胞核内分布增多 癌细胞。抑制L-纤溶酶的表达导致抑制 前列腺癌细胞的运动性和侵袭性。我们建议延长 这些研究旨在确定FGF8亚型和FGF8亚型之间的相互作用 成纤维细胞生长因子受体家族成员在间质和上皮中的表达 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。热休克蛋白1过表达的基础和潜能 它的亚细胞定位的新方面将被研究。 关于L-纤溶酶，我们会具体检查前列腺癌 高效率的组织可以抑制侵袭和转移 特异性反义L-纤溶酶基因的表达。为了延续我们的小说 腺体内和肿瘤内多发病例的发现 前列腺癌中P53突变的遗传异质性，我们也将 寻求确定是否出现P53突变以挽救缺氧性前列腺 癌细胞或来自具有p53突变的病灶区域的细胞是否有 有更高的转移倾向。这些研究结合在一起， 应该会为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 以新的方法治疗和/或管理这种疾病 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.