PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

该计划的长期目标是确定多个分子 在人类前列腺癌的发病机制中相互作用的事件。 我们 获得的证据表明， 前列腺癌的基因雄激素亚型的分子克隆- 诱导生长因子或FGF 8，在人前列腺癌细胞中表达， 进行了分离和表征。 对它们的功能研究 表明FGF 8表达有助于细胞的生物学行为， 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：HSF 1，热休克， 因子和L-纤维蛋白酶，肌动蛋白捆绑蛋白亚型。 核 转录因子HSF 1似乎主要定位于 低风险（B期）前列腺癌细胞的细胞质，而其 在高危（C期）前列腺的核中分布增加 癌细胞 抑制L-质体蛋白表达导致抑制 前列腺癌细胞的运动和侵袭。 我们建议扩大 这些研究旨在确定FGF 8同种型和 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 HSF 1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，我们将具体检查前列腺癌是否 高效、组织工程化的抗肿瘤药物能有效地抑制肿瘤的侵袭和转移， 特异性反义L-plastin基因表达。 来扩展我们的小说 发现腺内和瘤内的频繁发生 前列腺肿瘤中p53突变的遗传异质性，我们还将 试图确定p53突变是否会拯救缺氧的前列腺 癌细胞或来自具有p53突变的病灶区域的细胞是否具有 更容易转移 这些研究结合起来， 应该会对前列腺癌的发病机制有新的认识。 最终，对这些分子事件的理解将为我们提供 新的方法来治疗和/或管理这一问题， 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.