Growth Factors in Prostate Cancer

描述（由申请人提供）：前列腺癌是男性中最常见的恶性肿瘤（每年189,000例），在美国死亡率排名第二（30,200例）。由于寿命延长、对“癌症”的定义和检测不断变化以及对立即治疗的需求，社会和经济影响正在增加。了解从癌前激素反应相对良性状态到无法治愈的恶性肿瘤缓慢进展的步骤，对于预防和治疗危及生命的疾病至关重要。这个延续项目的假设是，上皮细胞间室的恶性进展是由基质和上皮之间的精确通信提供的共生稳态的逐渐破坏，其中FGF家族信号在其中起关键作用。FGF酪氨酸激酶受体复合物是由跨膜酪氨酸激酶、细胞周围基质硫酸肝素和FGF激活剂组成的三方复合物，它们产生细胞和组织特异性。FGF7、FGF10及其特异性FGFR同型FGFR2IIIb被分隔，介导从基质到上皮的定向特异性净稳态促进信号。硫酸肝素在FGF7和FGF10作用特异性中的结构基础和潜在作用将被确定。间质中FGF9对FGFR3（也可能是FGFR1）的信号传导将被表征为一种潜在的定向特异性的间质信号传导系统，该系统决定了间质细胞的表型，从而控制或允许癌前上皮的进展。我们将探索雄激素通过FGF家族影响基质和上皮之间双向区室特异性旁分泌信号传导，以及FGF信号传导影响雄激素反应的假设，这是克隆水平上促进和限制进展作用的基础。在不同恶性潜能和FGFR表型的克隆细胞类型中雄激素反应丧失的机制将被检查。这些目标将在细胞水平上进行探讨，在具有良好特征的Dunning体外/体内穿梭模型中，两室非恶性（癌前）肿瘤向一室恶性肿瘤的进展。将设计和利用具有FGFR信号复合物三个亚基改变的紧急小鼠遗传模型，以在生理背景下测试从前模型中吸取的经验教训。

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed malignancy in men (189,000 per year), and ranks second in mortality rate (30,200) in the USA. The social and economic impact is increasing as a consequence of increased lifespan, the changing definition and detection of the presence of "cancer" and demand for immediate treatment. Understanding the steps in the slow progression from a premalignant hormone responsive relatively benign state to incurable malignancy is essential for prevention and treatment of the life-threatening aspects of the disease. The hypothesis underlying this continuation project is that malignant progression in the epithelial compartment is a gradual upset in the symbiotic homeostasis provided by precise communication between stroma and epithelium in which FGF family signaling plays a key role. The FGF tyrosine kinase receptor complex is tripartite comprised of a transmembrane tyrosine kinase, pericellular matrix heparan sulfate and an FGF activator, which create cell- and tissue-context specificity. FGF7, FGF10 and their specific FGFR isotype, FGFR2IIIb, are partitioned to mediate directionally specific net homeostasis-promoting signals from stroma to epithelium. The structural basis and potential role of heparan sulfate in specificity of FGF7 and FGF10 action will be determined. FGF9 signaling to FGFR3 (and possibly FGFR1) in the stroma will be characterized as a potential directionally-specific epitheliium to the stroma signaling system that determines stromal cell phenotypes, which control or permit progression of premalignant epithelium. The hypothesis that androgen impacts two-way compartment-specific paracrine signaling between stroma and epithelium by the FGF family, and FGF signaling impacts androgen responsiveness that underlies windows of both progression-promoting and progression-limiting action at the clonal level will be explored. Mechanism of loss of androgen response in clonal cell types of different malignant potential and FGFR phenotype will be examined. These aims will be explored at the cellular level in the well-characterized Dunning in vitro/in vivo shuttle model of progression of two-compartment nonmalignant (premalignant) tumors to one compartment malignant tumors. Emergent mouse genetic models with alterations in the three subunits of the FGFR signaling complex will be designed and exploited to test lessons learned from the former model in physiological context.