Mechanisms and Markers of Prostate Cancer Metastases

本计划项目提案寻求对前列腺癌（CaP）进展和转移机制研究的支持。CaP现在是美国的头号癌症和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诊断和局部治疗，但对于进展性CaP没有治愈方法，其倾向于几乎完全转移到骨，并且在雄激素消融后转化为雄激素非依赖性状态。该提案分为4个项目和3个核心。项目I旨在使用现代基因组方法（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体中发现CaP进展期间新的和已知基因的表达模式，所述异种移植物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志物（包括CD 57和CD 44）的抗体纯化其基底和管腔细胞样特征。项目II旨在了解钙磷-骨相互作用的机制。该方法将在体外和体外检查几个因素的影响，在钙磷细胞，“允许”钙磷-骨植入，生长和/或独特的成骨细胞反应的发展。待检测的因子包括项目III中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（例如前列腺酶和TMPRSS 2）。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TPMRSS 2，并使用现代基因组技术发现和表征更多的这些蛋白酶。该项目还将确定这些新型蛋白酶中的任何一种是否可用作CaP的新血清标志物。项目IV旨在发现当CaP进展为雄激素非依赖性时，已知或新的生长因子，特别是与IGF系统相关的生长因子，如何影响雄激素受体或雄激素调节的信号通路的激活。项目之间的互动是众多的，并通过广泛的核心基础设施来促进。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。最后一个核心小组提供全面的行政支助。

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.