Growth Factors in Prostate Cancer

描述(申请人提供)：前列腺癌是男性最常见的恶性肿瘤(每年189,000例)，在美国死亡率(30,200例)排名第二。由于寿命的延长、对“癌症”存在的定义和检测的改变以及对立即治疗的需求，对社会和经济的影响正在增加。了解从癌前激素应答的相对良性状态到不可治愈的恶性肿瘤缓慢进展的步骤，对于预防和治疗该病威胁生命的方面至关重要。这一继续项目的假设是，上皮间隔室的恶性进展是由基质和上皮之间的精确沟通所提供的共生稳态的逐渐破坏，而成纤维细胞生长因子家族信号在其中起着关键作用。成纤维细胞生长因子酪氨酸激酶受体复合体由一个跨膜酪氨酸激酶、细胞周围基质硫酸乙酰肝素和成纤维细胞生长因子激活剂三部分组成，它们创造了细胞和组织的特异性。FGF7、FGF10及其特异的FGFR亚型FGFR2IIIb被分割，以介导从基质到上皮的定向特异性净稳态促进信号。硫酸乙酰肝素在Fgf7和FGF10作用的特异性中的结构基础和潜在作用将被确定。间质中FGFR3(可能还有FGFR1)的FGF9信号将被描述为决定基质细胞表型的基质信号系统的潜在方向特异性上皮细胞，该信号系统控制或允许癌前上皮的进展。假设雄激素通过成纤维细胞生长因子家族影响间质和上皮之间的双向隔室特异性旁分泌信号，以及成纤维细胞生长因子信号影响雄激素反应，这是在克隆水平上促进和限制进展作用的窗口。不同恶性潜能和FGFR表型的克隆细胞中雄激素反应丧失的机制将被研究。这些目标将在细胞水平上探索，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进展。具有FGFR信号复合体三个亚单位改变的紧急小鼠遗传模型将被设计和利用，以在生理背景下测试从前一个模型中学到的教训。

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.