PROSTATE-CANCER - BIOLOGY OF METASTASIS AND ITS CLINICAL IMPLICATIONS

Prostate cancer is one of the most commonly diagnosed cancers and is a major cause of cancer death in men. Although the majority of the diag nosed prostate cancers will remain localized and never produce clinica l symptoms during the lifetime of the host, a subset of these cancers will progress to a more malignant state requiring therapeutic interven tion. Acquisition of metastatic ability by prostatic cancer cells is t he most lethal aspect of prostatic cancer progression. Once this has o ccurred, definitive therapy is required before the initially localized metastatic cells escape from the prostate. At present, metastatic pro state cancer is incurable. Therefore, there is an urgent need to devel op molecular markers that can be used to predict the metastatic potent ial of prostate cancers. Using somatic cell hybridization, we have dem onstrated that acquisition of metastatic ability requires both the los s of metastasis-suppressor funct ion(s) and the activation of oncogene s. In further studies using microcell-mediated chromosomal transfer, w e located genes on human chromosome, 8, 10cen-q23, 11p11.2-13, and 17p ter-q23, which, when introduced into rat prostatic cancer cells, are c apable of suppressing their metastatic ability without affecting their tumorigenicity or growth rate in vivo. Initially we focused upon the human chromosome 11p11.2-13 region to clone metastasis-suppressor gene (s) positionally. One such gene, termed KAI-1, encodes a membrane glyc oprotein. KAI-1 has been mapped to the p11.2 region of human chromosom e II by fluorescence in-situ hybridization analysis. Expression of KAI -1 has been detected in all normal human tissues thus far tested, incl uding prostate tissue. When introduced into rat metastatic prostatic c ancer cells, KAI-1 significantly suppressed the metastasis without aff ecting the tumor growth rate, KAI-1 expression is high in human normal prostate and benign prostatic hyperplasia but is dramatically lower i n cancer cell lines derived from metastatic prostate tumors.