Growth Factors in Prostate Cancer

描述（由申请人提供）：前列腺癌是男性中最常诊断的恶性肿瘤（每年189，000例），在美国死亡率排名第二（30，200例）。由于寿命的延长、“癌症”定义和检测的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性相对良性状态到无法治愈的恶性肿瘤的缓慢进展中的步骤对于预防和治疗该疾病的危及生命的方面至关重要。该延续项目的基础假设是，上皮区室中的恶性进展是基质和上皮之间精确通信所提供的共生体内平衡的逐渐破坏，其中FGF家族信号传导起关键作用。FGF酪氨酸激酶受体复合物由跨膜酪氨酸激酶、细胞周基质硫酸乙酰肝素和FGF激活剂组成，其产生细胞和组织环境特异性。FGF 7、FGF 10及其特异性FGFR同种型FGFR 2 IIIb被分配以介导从基质到上皮的定向特异性净稳态促进信号。将确定硫酸乙酰肝素在FGF 7和FGF 10作用特异性中的结构基础和潜在作用。间质中FGF 9信号传导至FGFR 3（和可能的FGFR 1）将被表征为间质信号传导系统的潜在方向特异性上皮，其决定间质细胞表型，其控制或允许癌前上皮的进展。雄激素通过FGF家族影响基质和上皮之间的双向室特异性旁分泌信号传导，FGF信号传导影响雄激素反应性，这是克隆水平上促进进展和限制进展作用的基础。将检查不同恶性潜能和FGFR表型的克隆细胞类型中雄激素反应丧失的机制。将在充分表征的Dunning体外/体内穿梭模型中在细胞水平上探索这些目标，该模型将两室非恶性（癌前）肿瘤进展为一室恶性肿瘤。将设计和利用FGFR信号复合物的三个亚基发生改变的紧急小鼠遗传模型，以测试从生理背景下的前一个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.