Mechanisms and Markers of Prostate Cancer Metastases

前列腺癌转移的机制和标志物

• 批准号: 6744318
• 负责人: PAUL H. LANGE
• 金额: $ 211.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744318
• 关键词: clinical research; genetic markers; metastasis; molecular oncology; neoplastic process; patient oriented research; prostate neoplasms

This program project proposal seeks support for studies on the mechanisms of progression and metastasis of progression and metastasis in carcinoma of the prostate (CaP). CaP is now the nation's #1 cancer and the #2 cancer killer in men. While prostatic specific antigen has revolutionized diagnosis and local therapies, there is no cure for progressive CaP which tends to metastasize almost exclusively to bone and to convert to an androgen independent state following androgen ablation. The proposal is divided into 4 Projects, and 3 Cores. Project I seeks to discover the expression patterns of new and known genes during CaP progress using modern genomic approaches (cDNA libraries, sequencing, microassays) in populations of cells from a variety of CaP tissues and xenograft purified for their basal and luminal cell-like characteristics using high through-put cell sorting techniques and antibodies to a variety of established cell surface markers including CD57 and CD44. Project II seeks to learn about the mechanisms of CaP-bone interactions. The approach will be to examine in vitro and in vitro the influence of several factors in CaP cells that "allow" CaP-bone implantation, growth and/or the development of the unique osteoblastic response. The factors to be examined include the newly discovered bone regulatory proteins Osteoprotegerin, TRANCE and RANK, the insulin-like growth factor (IGF) and endothelin-1 and the newly discovered prostate specific serine proteases (e.g. Prostase and TMPRSS2) of Project III. Project II seeks to learn more about their two recently discovered prostate specific serine proteases Prostase and TPMRSS2 and to discover and to characterize more of these proteases using modern genomic techniques. The project will also determine whether any of these novel proteases can be used as new serum markers for CaP. Project IV seeks to discovery how known or new growth factors, especially those associated with the IGF system, influence the activation of the androgen receptor or androgen-regulated signaling pathways when CaP progresses to androgen independence. The interactions among the projects are numerous and are facilitated by an extensive Core infrastructure. One Core provides 5 services including specimen acquisition and execution of all xenograft activities. Another Core provides genomic support. The final Core provides comprehensive administrative support.

该计划项目提案寻求对前列腺癌（CaP）进展和转移机制的研究的支持。目前，CaP 是美国第一大癌症，也是男性第二大癌症杀手。虽然前列腺特异性抗原彻底改变了诊断和局部治疗，但进行性 CaP 无法治愈，这种疾病几乎完全转移到骨骼，并在雄激素消融后转化为雄激素独立状态。该提案分为 4 个项目和 3 个核心。项目 I 试图利用现代基因组方法（cDNA 文库、测序、微量测定）在来自各种 CaP 组织和异种移植物的细胞群中发现 CaP 进展过程中新的和已知的基因的表达模式，这些细胞的基础和腔细胞样特征经过纯化使用高通量细胞分选技术和针对多种已建立的细胞表面标记物（包括 CD57 和 CD44）的抗体。项目 II 旨在了解 CaP-骨相互作用的机制。该方法将在体外检查 CaP 细胞中几种因素的影响，这些因素“允许”CaP 骨植入、生长和/或独特的成骨细胞反应的发展。待检测的因子包括Project III新发现的骨调节蛋白Osteoprotegerin、TRANCE和RANK、胰岛素样生长因子（IGF）和内皮素-1以​​及新发现的前列腺特异性丝氨酸蛋白酶（例如Prostase和TMPRSS2）。项目 II 旨在更多地了解他们最近发现的两种前列腺特异性丝氨酸蛋白酶 Prostase 和 TPMRSS2，并利用现代基因组技术发现和表征更多这些蛋白酶。该项目还将确定这些新型蛋白酶是否可以用作 CaP 的新血清标记物。 Project IV 旨在发现当 CaP 进展为雄激素独立时，已知或新的生长因子（尤其是与 IGF 系统相关的生长因子）如何影响雄激素受体或雄激素调节信号通路的激活。项目之间的交互有很多，并由广泛的核心基础设施促进。 One Core 提供 5 项服务，包括标本采集和所有异种移植活动的执行。另一个核心提供基因组支持。最终的核心提供全面的管理支持。