MECHANISMS OF METASTASIS IN EXPERIMENTAL PROSTATE CANCER

描述：（改编自研究者摘要） 前列腺癌的死亡率是由于前列腺癌细胞的明显或 最终表现为雄激素抵抗性疾病的隐匿性转移。到 为了更好地了解前列腺癌的转移表型，他开发了一种 鉴定细胞系中差异表达的mRNA的策略 来自原发性与转移性小鼠前列腺癌， 显示PCR。在使用该系统时，一些转移相关基因被 鉴定了包括编码小窝蛋白-1的cDNA。Caveolin-1被发现是 不仅在转移性小鼠前列腺癌中过表达， 转移性疾病，并被证明是复发的独立预测因子 在根治性直肠切除术后小窝蛋白-1表达的抑制诱导 高小窝蛋白-1、雄激素不敏感小鼠前列腺的雄激素敏感性 癌细胞来源于转移。相反，过度表达小窝蛋白-1 导致低caveolin-1雄激素敏感小鼠雄激素不敏感 前列腺癌细胞他证明睾丸激素诱导小窝蛋白-1 通过转录调控表达，并且小窝蛋白-1是一种 睾丸激素诱导小鼠前列腺癌存活的下游效应子 体外细胞他在人类前列腺癌标本中证实， 小窝蛋白-1的表达在原发性肿瘤中显著增加， 化学和手术雄激素消融后的转移， 初步研究表明，特定的生长因子可能诱导小窝蛋白-1 在缺乏睾酮的情况下表达维持细胞存活。一个关键 小窝蛋白-1与前列腺癌进展之间的分子联系， 通过发现c-myc过表达导致 下调小窝蛋白-1阻断c-myc诱导的体外细胞凋亡。他现在 提出了表征小窝蛋白-1基因表达的调控， 基因甲基化、睾酮和生长因子介导的前列腺癌 机制等他还将定义小鼠中的顺式作用调控元件 小窝蛋白-1启动子介导转录激活。基于 初步数据表明，caveolin-1可以特异性地防止 他将绘制出产生的生化模块 Caveolin-1的。最后，他将测试潜在的合作活动， c-myc和caveolin-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.