Identification of metastasis suppressor genes for prostate cancer and establishment of genetic diagnosis and therapeutic system of prostate cancer.

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Identification of molecular and cellular markers for the progression of prostate cancer would be useful in developing diagnostic methods for substaging prostate cancers. To isolate such genes, I have established a rat prostate cancer system. Clinical specimens have been also examined to identify molecular markers.By using the rat system, I have isolated the 60-kb fragment from 8p21-22 region, which contains the metastasis suppressor gene. This metastasis suppressor gene did not seem to be translated to a protein. By using the same method, I have shown that human chromosome 13 contains metastasis suppressor gene(s). I have also examined the mechanism of metastasis-suppressing function by human chromosome 10.In order to isolate homogeneous cancerous tissue form prostate cancer specimens, laser capture microdissection system was utilized. DNA of high quality was extracted from the microdissected tissue and was genetically analyzed. Comparative genomic hybridization analysis demonstrated that frequent losses of 2q,4q,6q,8p,13q,16q,and 18q. Losses of 8p and 13q were observed more frequently in the pT3 tumors than pT2. A loss of 13q was observed more frequently in the tumors with Gleason score 7 or more. A loss of 6q was related with biochemical recurrence. These regions identified by the CGH analysis were essentially same as those previously identified by the PCR-LOH analysis. In this study, I have also performed the conventional PCR-LOH analysis and have found frequent losses at 12p13-12,2p16.3,2p12-cen,2q21.3,and 2q23.1-32.1 of the cases with advanced cancer.I have reviewed the previous studies on development of hormone-refractory prostate cancer, and found that there are two major pathways, androgen receptor (AR)-dependent pathway and AR-independent pathway. I have also performed clinical studies in order to apply the molecular data above to the bedside.