Pathogenesis of human prostate carcinomas

描述（由申请人提供）：已经确定了许多与人类前列腺癌自然相关的遗传畸变。为了研究前列腺癌的发病机制，合理地将这一知识应用于小鼠前列腺癌的建模，以重现前列腺癌的自然历史和临床过程。从模型中获得的线索可以用适当的人类前列腺细胞系统和病变来检验它们的相关性或有效性。这种综合和平行的研究可能会对这种常见疾病的发病机制产生新的见解。我们已经启动或计划的工作考虑了三种特定的遗传畸变，它们是生长因子FGF8的激活，同种异构体b；类视黄醛受体功能不足；Pten肿瘤抑制基因失活。这一重点的前提是认识到这些畸变之间的信号传导的遗传协同作用，这些畸变聚集在一起，驱动细胞增殖和生存。我们假设，关于这些畸变的日益复杂的小鼠模型的连续发展应该为研究导致前列腺癌发生和发展的分子机制提供重要的机会。基于我们在前列腺上皮中FGF8过表达或rxrα受体失活的单一模型中发现的类似前列腺癌早期阶段的组织病理学缺陷，我们的第一个目标是确定FGF8b的有效性；rxrα复合突变小鼠用于前列腺肿瘤发生的研究。在第二个目标中，我们建议从信号缺陷或发病机制的角度来描述单个模型中前列腺叶特异性分泌蛋白的改变，并定义在FGF8b或复合模型中观察到的基质增殖的基础。最后，第三个目标是将Pten缺乏结合到可能发展为腺癌的三突变小鼠中，以分析候选信号分子和前列腺叶特异性基因在雄激素依赖性癌症发展过程中的表达变化，并可能进一步发展为转移性病变。

DESCRIPTION (provided by applicant): A number of genetic aberrations that naturally associate with human prostate cancer has been identified. To study the disease mechanism, one approach is to apply this knowledge rationally in modeling prostate cancer in mice in order to recapitulate the natural history and clinical course of the disease. Clues obtained from the models could then be examined for their correlation or validity using appropriate human prostatic cell systems and lesions. Such integrated and parallel investigations are likely to yield new insights into the pathogenesis of this common disease. The work we have initiated or planned considers three specific genetic aberrations, which are activation of a growth factor, FGF8, isoform b; deficiency in retinoid receptor function; and inactivation of Pten tumor suppressor gene. The premise of this focus is on the recognition of genetic synergy in signaling between these aberrations that converges to drive cell proliferation and survival. We hypothesize that successive development of increasingly complex mouse models with respect to these aberrations should provide significant opportunities for studying the molecular mechanisms that lead to genesis and progression of prostate cancer. Based on our findings of histopathological defects that resemble early stages of prostate cancer in single models from FGF8 overexpression or RXRalpha receptor inactivation in the prostate epithelium, our first aim is to determine the validity of the FGF8b; RXRalpha compound mutant mice for the study of prostate tumorigenesis. In the second aim, we propose to characterize the altered prostatic lobe-specific secretory proteins in the individual single models in terms of signaling defects or pathogenesis, and define the basis for the observed stromal proliferation in the FGF8b or compound model. Finally, the third aim concerns incorporation of Pten deficiency to derive triple mutant mice, likely to progress beyond adenocarcinoma, for the analyses of candidate signaling molecules and prostate lobe-specific gene expression changes in progression to androgen-dependent cancer, and potentially further to metastatic lesions.