GROWTH FACTORS IN PROSTATE CANCER

前列腺癌是男性最常见的恶性肿瘤， 死亡率在美国排名第二，仅次于肺癌。癌症和 良性前列腺增生症(BPH)是一种日益增长的社会经济现象 随着男性寿命的增加，给医疗保健系统带来了负担。 前列腺癌是渐进性的，但主要发生在 两个阶段。I型癌症在很大程度上对抗雄激素敏感 治疗，但长期进展为II型恶性和 无法治愈的状态。对类型渐进式转换的理解 I型到II型状态迫切需要指导诊断、预防 和治疗。这个延续项目背后的假设是 从非恶性状态到恶性状态的进展是一种 体内平衡的阶段性破坏是由 前列腺的上皮和间质。肝素结合性成纤维细胞 生长因子家族多肽及其受体(FGF-R)具有 被坚定地牵涉到调解内部的生长和分化 前列腺。成纤维细胞生长因子家族是一个极其异质性的三个家族 组成系统-成纤维细胞生长因子多肽、成纤维细胞生长因子受体激酶和成纤维细胞生长因子肝素 硫酸盐蛋白多糖。这个项目将确定分子和 调节动态平衡的细胞机制(生长，生长 抑制/死亡和分化)由特定的成纤维细胞生长因子成员 前列腺癌的家族和进展过程中发生的变化 恶毒。具体地说，项目将确定(1)具体的 间质来源的成纤维细胞生长因子-7和成纤维细胞生长因子-10在上皮细胞调控中的作用 表型；(2)成纤维细胞生长因子变化的时间进程和顺序 癌前病变上皮细胞进展过程中的信号系统 细胞向恶性转化；(3)细胞外和细胞内的相对作用 FGFR1和FGFR2结构域在这一过程中的作用；(4)雄激素的作用及其机制 鳞状细胞与腺体分化中的受体；(5)结构 FGFR1和FGFR2中的基序在非恶性和非恶性肿瘤中的潜在作用 恶性细胞表型；(6)特定周围期变化的影响。 细胞硫酸乙酰肝素；(7)调节交替的条件 FGFR2基因的剪接。最后，该项目将使用鼠标 遗传学检测FGFR1和FGFR2对机体的生理影响 前列腺癌的进展。这些成果将为以下工作开辟新的途径 前列腺癌进展潜能的早期诊断 预防进展和治疗针对以下目标的恶性肿瘤 FGFR信号系统。

Prostate cancer is the most commonly diagnosed malignancy in men, and ranks second in mortality rate after lung cancer in the USA. Cancer and benign prostatic hyperplasia (BPH) is an increasing socio-economic burden on the medical care system with increase in life span of males. Prostate cancer is progressive to malignancy, but occurs primarily in two stages. Type I cancers are largely responsive to anti-androgen treatment, but over long periods progress to the type II malignant and untreatable state. Understanding of the progressive transition from type I to type II states is urgently needed to guide diagnosis, prevention and treatment. The hypothesis underlying this continuation project is that the progression from the non-malignant to malignant states is a stepwise disruption of homeostasis mediated by communication between epithelium and stroma of the prostate. The heparin-binding fibroblast growth factor (FGF) family of polypeptides and its receptor (FGF-R) has been firmly implicated in mediation of growth and differentiation within the prostate. The FGF family is an extremely heterogenous three component system-FGF polypeptides, FGF receptor kinase and FGF heparan sulfate proteoglycan. This project will determine the molecular and cellular mechanisms underlying mediation of homeostasis (growth, growth inhibition/death and differentiation) by specific members of the FGF family in prostate and the changes that occur during progression to malignancy. Specifically, the project will determine (1) the specific roles of stromal derived FGF-7 and FGF-10 in instruction of epithelial phenotypes; (2) the time course and sequence of changes in the FGF signaling system during progression of pre-malignant tumor epithelial cells to malignancy; (3) relative roles of the ecto- and intracellular domains of FGFR1 and FGFR2 in the process; (4) role of androgen and its receptor in squamous versus glandular differentiation; (5) structural motifs in FGFR1 and FGFR2 underlying effects on non-malignant and malignant cell phenotypes; (6) impact of changes in specific peri- cellular heparan sulfates; (7) conditions that regulate alternate splicing of the FGFR2 gene. Lastly, the project will employ mouse genetics to test the physiological consequence of FGFR1 and FGFR2 on prostate tumor progression. These results will open up new avenues for early diagnosis of prostate tumor potential for progression, for prevention of progression and for treatment of malignancies targeted to the FGFR signaling system.