Progression of cancer to the metastatic state involves multiple cellular and genetic changes. Using somatic cell hybridization, we demonstrated that acquisition of metastatic ability requires both the loss of metastasis suppressor functions and the activation of oncogenes. We cloned a gene, termed KAI1, that can suppress the metastatic ability of a rat prostatic cancer cell line. We found that KAI1 is highly expressed in normal prostate and breast epithelial cells but is dramatically lower in cancer cell lines derived from metastatic tumors. We also found reduced or altered protein expression in human bladder, endometrial, lung, colon, ovarian, and melanoma cancer cell lines. We are currently developing new antibody reagents that will allow study of KAI1 expression in archived tissue sections. We have collected primary and metastatic tumor specimens from prostate, colon, breast, and ovarian tumors to investigate whether KAI1 expression can be used to predict the metastatic ability of primary cancers. We completed studies that show that KAI1 is downregulated in neoplasms of the colon. We have also been identifying KAI1 binding partners in order to determine how they may regulate KAI1 function. We identified that E- cadherin, catenins, and integrins all complex with KAI1. We have examined the role of KAI1 in cell-cell aggregation, adhesion, and invasion using in vitro assays. Finally, we are developing in vivo metastasis assays using a variety of injection sites to test the ability of KAI1 to suppress multiple cells at various stages of the metastatic process. Finally, we are using a combination of cloning techniques to clone another prostate metastasis suppressor gene on chromosome 8p. Current efforts are focused on a BAC that we have shown contains functional activity, capturing the cDNAs within, and ultimately identifying this candidate gene. - KAI1, metastasis, metastasis suppression, prostate cancer, e-cadherin
