GROWTH FACTORS IN PROSTATE CANCER

前列腺癌的生长因素

• 批准号: 2704388
• 负责人: WALLACE LEE MCKEEHAN
• 金额: $ 21.93万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-11-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2704388
• 关键词: androgens; biological signal transduction; cell differentiation; cell growth regulation; cell line; chromatography; epithelium; fibroblast growth factor; gene expression; growth factor receptors; heparin; hormone regulation /control mechanism; laboratory mouse; laboratory rat; neoplastic growth; neoplastic process; phenotype; prostate neoplasms; protein structure function; tissue /cell culture

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.

前列腺癌是男性最常见的恶性肿瘤， 在美国死亡率仅次于肺癌。癌症和 良性前列腺增生（BPH）是一种日益严重的社会经济疾病， 随着男性寿命的延长，医疗保健系统的负担加重。 前列腺癌进展为恶性，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有反应 治疗，但长期发展为II型恶性肿瘤， 无法治愈的状态理解从类型的渐进过渡 I型到II型状态是迫切需要指导诊断、预防 和治疗。 这个延续项目的假设是 从非恶性到恶性的发展过程 内环境稳定的逐步破坏，由两个细胞之间的交流介导， 前列腺的上皮和基质。 肝素结合成纤维细胞 生长因子（FGF）家族多肽及其受体（FGF-R）具有 它与生长和分化的中介密切相关， 前列腺成纤维细胞生长因子家族是一个极其异质的三个家族 组成系统--FGF多肽、FGF受体激酶和FGF类肝素 硫酸化蛋白聚糖。 该项目将确定分子和 体内平衡（生长、生长、发育）的细胞调节机制 抑制/死亡和分化）的特定成员 前列腺中的家族和进展过程中发生的变化 恶性肿瘤 具体而言，该项目将确定（1）具体 间质源性FGF-7和FGF-10在上皮细胞分化中的作用 表型;（2）FGF变化的时间过程和顺序 癌前上皮性肿瘤进展过程中的信号系统 细胞恶性肿瘤;（3）相对作用的外-和细胞内 FGFR 1和FGFR 2的结构域在该过程中的作用;（4）雄激素及其 受体在鳞状细胞与腺分化;（5）结构 FGFR 1和FGFR 2中的基序对非恶性肿瘤和 恶性细胞表型;（6）特定肿瘤细胞表型变化的影响， 细胞硫酸乙酰肝素;（7）调节交替的条件 FGFR 2基因的剪接。最后，该项目将采用鼠标 遗传学来测试FGFR 1和FGFR 2对 前列腺肿瘤进展。 这些结果将为以下方面开辟新的途径： 早期诊断前列腺肿瘤的进展潜力， 预防疾病进展和治疗恶性肿瘤， FGFR信号系统