Integrin-Mediated Signaling in Prostate Cancer: Role of KAI1/CD82 in Regulating Integrin and Androgen Receptor Function During Metastasis
Final rept. 31 Mar 2004-31 Aug 2007
VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI
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How prostate tumors become metastatic is virtually unknown. A prostate metastasis suppressor gene, KAI1CD82, known to associate with laminin receptors, allowed us to test the hypothesis that loss of KAI1CD82 expression alters the function of laminin integrins in prostate cancer cells, resulting in altered intracellular signaling and increased invasion leading to metastasis. We have demonstrated that in metastatic tumor cells, where elevated c-Met expression and activation by integrins is responsible for enhancing laminin-dependent migration and invasion, re-expression of CD82 suppresses, while loss of CD82 enhances c-Met activation. Orthotopic injection of CD82-expressing metastatic cells into mouse prostates suppresses both metastasis and growth in vivo. CD82 appears to regulate c-Met activation by altering the distribution of c-Met on the cell surface, possibly through CD82 association with another tetraspanin, CD9, and their joint association with PI integrin. Our studies have advanced the knowledge of how members of the tetraspanin family function and are potentially applicable to all metastatic disease, since KAI1CD82 loss has been reported in many types of cancers. Our results suggest that targeting c-Met would be a logical approach to therapeutic intervention of metastatic disease. Our findings further suggest that together CD82 expression and c-Met activation could be used as a potential biomarker pair for the prediction of metastatic disease. In addition we have shown that the PI-3KAkt pathway is critical for laminin-specific survival in metastatic prostate cells, but activation of the androgen receptor AR by-passes the need for PI-3K signaling when cells are adherent to laminin. Since over 90 of metastatic prostate cancers still express AR, targeting the PI-3K pathway alone would not be sufficient to kill tumors in a laminin-rich environment.
- Medicine and Medical Research