MECHANISMS OF METASTASIS IN EXPERIMENTAL PROSTATE CANCER

描述：(改编自调查人员的摘要)高水平的 前列腺癌的死亡率是由于前列腺癌或前列腺癌患者 隐匿性转移最终表现为雄激素抵抗疾病。至 为了更好地了解前列腺癌的转移表型，他开发了一种 识别在细胞系中差异表达的mRNAs的策略 从原发和转移性小鼠前列腺癌来源的差异 显示-聚合酶链式反应。在使用该系统时，许多与转移相关的基因被 鉴定出包括编码小窝蛋白-1的cdna。洞穴-1号被发现是 不仅在转移性小鼠前列腺癌中过表达，而且在人类中也过表达 转移性疾病，被证明是复发的独立预测因素 在根治性前列腺切除术后。抑制小窝蛋白-1的表达诱导 雄激素不敏感小鼠前列腺对雄激素敏感性的研究 癌细胞来源于转移。相反，小窝蛋白-1的过表达 导致低窝蛋白-1雄激素敏感小鼠的雄激素不敏感 前列腺癌细胞。他证明了睾丸激素可以诱导小窝蛋白-1 表达通过转录调控，小窝蛋白-1是一个 睾酮诱导小鼠前列腺癌存活的下游效应因子 体外培养的细胞。他在人类前列腺癌样本中证实 小窝蛋白-1在原发肿瘤和非小细胞肺癌中的表达均显著增加 化疗和外科雄激素消融后的转移，以及 初步研究表明，特定的生长因子可能诱导小窝蛋白-1 在缺乏支持细胞存活的睾丸激素的情况下表达。一位批评者 小窝蛋白-1与前列腺癌进展之间的分子联系是 通过发现c-myc的过度表达导致 Caveoline-1的下调可在体外阻断c-myc诱导的细胞凋亡。他现在 建议对小窝蛋白-1基因表达的调控进行表征 基因甲基化、睾酮和生长因子介导的前列腺癌 机械装置。他还将定义老鼠体内的顺式作用调节元件 介导转录激活的小窝蛋白-1启动子。基于 初步数据表明小窝蛋白-1可以特异性地预防 Thapsigargin诱导的细胞死亡，他将映射产生的生化区块 由小穴-1。最后，他将测试潜在的合作活动 C-myc和小窝蛋白-1在体内外促恶性进展中的作用 使用LNCaP-mycer系统和转基因前列腺和小鼠模型。

DESCRIPTION: (Adapted from the investigator's abstract) The high level of mortality from prostate cancer results from the inexorable growth of overt or occult metastases that ultimately manifest as androgen resistant disease. To better understand the metastatic phenotype in prostate cancer, he developed a strategy to identify mRNAs that are expressed differentially in cell lines derived from primary versus metastatic mouse prostate cancer using differential display-PCR. In using this system, a number of metastasis-related genes were identified including a cDNA that encodes caveolin-1. Caveolin-1 was found to be overexpressed not only in metastatic mouse prostate cancer, but also in human metastatic disease and was shown to be an independent predictor of recurrent following radical prostatectomy. Suppression of caveolin-1 expression induces androgen sensitivity in high caveolin-1, androgen-insensitive mouse prostate cancer cells derived from metastases. Conversely, overexpression of caveolin-1 leads to androgen instensitivity in low caveolin-1 androgen-sensitive mouse prostate cancer cells. He demonstrate that testosterone induces caveolin-1 expression through transcriptional regulation, and that caveolin-1 is a downstream effector for testosterone-induced survival in mouse prostate cancer cells in vitro. He has confirmed in human prostate cancer specimens that caveolin-1 expression is significantly increased in both primary tumors and their metastases following chemical and surgical androgen ablation, and preliminary studies suggest specific growth factors may induce caveolin-1 expression in the absence of testosterone sustaining cell survival. A critical molecular link between caveolin-1 and prostate cancer progression was established through the discovery that c-myc overexpression leads to downregulation of caveoline-1 blocks c-myc-induced apoptosis in vitro. He now proposes to characterize the regulation of caveolin-1 gene expression in prostate cancer by gene methylation, testosterone and growth factor-mediated mechanisms. He will also define the cis-acting regulatory elements in the mouse caveolin-1 promoter that mediate transcriptional activation. Based on preliminary data that indicate caveolin-1 can specifically protect against thapsigargin-induced cell death, he will map the biochemical blocks generated by caveolin-1. Finally, he will test the potential cooperative activities of c-myc and caveolin-1 in promoting malignant progression in vitro and in vivo using an LNCaP-mycER system and transgenic prostate and mouse models.