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.
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