Mechanisms and Markers of Prostate Cancer Metastases

本项目旨在支持前列腺癌（CaP）进展和转移机制的研究。CaP现在是美国的头号癌症，也是男性的第二大癌症杀手。虽然前列腺特异性抗原已经彻底改变了前列腺癌的诊断和局部治疗方法，但目前还没有治愈进展性前列腺癌的方法，因为前列腺癌倾向于几乎完全转移到骨，并在雄激素消融后转变为雄激素独立状态。该提案分为4个项目和3个核心。项目一旨在利用现代基因组方法（cDNA文库、测序、微分析），在各种CaP组织和异种移植物的细胞群体中发现CaP进展过程中新的和已知基因的表达模式，这些细胞群体使用高通量细胞分选技术和针对各种已建立的细胞表面标记物（包括CD57和CD44）的抗体，纯化其基础和管状细胞样特征。项目II旨在了解CaP-bone相互作用的机制。该方法将在体外和体外检查CaP细胞中几个因素的影响，这些因素“允许”CaP骨植入、生长和/或形成独特的成骨细胞反应。检查因子包括新发现的骨调节蛋白Osteoprotegerin、TRANCE、RANK，胰岛素样生长因子（IGF）、内皮素-1，以及III项目新发现的前列腺特异性丝氨酸蛋白酶（如Prostase、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。该项目还将确定是否有任何这些新型蛋白酶可以用作CaP的新的血清标志物。第四项目旨在发现已知或新的生长因子，特别是与IGF系统相关的生长因子，如何在CaP发展到雄激素独立时影响雄激素受体的激活或雄激素调节的信号通路。项目之间的互动是众多的，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Core提供基因组支持。最终的Core提供全面的管理支持。

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.