From 20-40 percent of men who undergo a radical prostatectomy for localized disease later relapse with progressive disease that invariably results in bone metastases. Despite enormous efforts in the analysis of the primary tumor, few prognostic markers have been revealed. We have focused attention on the detection and isolation of disseminated CaP cells in the blood and bone marrow (BM). Our belief is that these disseminated cells, particularly those in the BM, may provide critical insight to the processes of progression. It would appear logical that the CaP cells in the BM that remain following a radical prostatectomy may be more informative than those of the primary tumor which is removed at surgery. Yet, the detection of these cells and especially their recovery for study has been heretofore most challenging. Our group has devoted a considerable effort to both of these tasks and this proposal is the result of successes in these endeavors. Our data reveal that approximately 65 percent of patients who undergo a radical prostatectomy have disseminated PSA+ cells in their BM prior to surgery. In this proposal we will expand our studies from the simple detection of disseminated cells to their characterization. In addition to standard immunohistochemistry, the analyses will utilize state-of-art techniques in gene expression micro-arrays and array Comparative Genomic Hybridization (array-CGH). We will use these approaches to test three major hypotheses: (1) Disseminated CaP cells isolated from the BM at the time of radical prostatectomy will reveal biological features useful in assessing the robability of relapse. These features will become evident by a comprehensive comparison of the results of whole-genome scans for karyotypic alterations and changes in gene expression levels in pools of disseminated cells isolated from patients at different stages of progression. (2) Residual disseminated CaP cells in the BM will provide more insight into recurrences than the primary tumor that is removed at surgery. Comparisons of karyotypic and gene expression profiles of bone metastases within and among patients will reveal common alterations in molecular pathways relevant to progression and growth in bone. (3) The characteristics of disseminated cells, particularly those related to gene expression levels, will modulate as a result of treatment. These studies will provide the first multiparametric analyses of disseminated cells that takes advantage of advances in (a) the isolation and recovery of disseminated CaP cells from bone marrow, (b) cutting edge technologies in expression micro-arrays and array-CGH, and an extensive and comprehensive SPORE infrastructure that will provide the critical statistical and informatics support.
Showing the most recent 10 out of 400 publications
