Mechanisms and Markers of Prostate Cancer Metastases

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。CAP现在是美国头号癌症患者和第二大男性癌症杀手。虽然前列腺特异性抗原使诊断和局部治疗发生了革命性的变化，但对于进行性前列腺帽，几乎只会转移到骨骼，并在雄激素消融后转变为雄激素非依赖性状态，目前还没有治愈的方法。该提案分为4个项目，3个核心。项目I试图使用现代基因组学方法(cDNA文库、测序、显微分析)在CAP进展过程中发现新基因和已知基因的表达模式，这些细胞群体来自各种CAP组织和异种移植，利用高通量细胞分选技术和对包括CD57和CD44在内的各种已建立的细胞表面标记的抗体进行纯化，以获得其基础和腔细胞样特性。项目II试图了解帽子-骨骼相互作用的机制。该方法将在体外和体外检测几种因素对帽细胞的影响，这些因素“允许”帽骨植入、生长和/或发展独特的成骨反应。将被检查的因素包括项目III中新发现的骨调节蛋白OsteoProggerin、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(如Prostase和TMPRSS2)。项目II试图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鉴定更多这些蛋白。该项目还将确定这些新型蛋白酶中是否有任何一种可以用作CAP的新血清标记物。项目IV试图发现当CAP进展到雄激素非依赖性时，已知或新的生长因子，特别是那些与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，并由广泛的核心基础设施促进。One Core提供5项服务，包括所有异种移植活动的标本获取和执行。另一个核心提供基因组支持。最终核心提供全面的行政支持。

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.