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2008 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Role of androgen receptor in integrin-mediated survival All primary and metastatic prostate cancers express the intracellular steroid receptor for androgen (AR). In the normal gland, the AR-expressing cells do not interact with the ECM in the basement membrane; however, all AR-expressing tumor cells do adhere to the ECM in the basement membrane. In normal cells, AR expression suppresses growth and promotes differentiation, but in tumor cells AR expression promotes cell growth and is required for cell survival. The mechanisms that lead to the change from growth inhibition and differentiation to growth promotion and survival are unknown. Our hypothesis is that adhesion to the ECM by the tumor cells is responsible for driving the change in AR function by initiating crosstalk between AR and integrins. When prostate tumor cells are placed in culture, they lose expression of AR. The reason for this is not clear, but it may have to do with loss of the appropriate ECM-containing basement membrane. When we introduce AR into prostate tumor cells, it actually suppresses their growth and induces cell death. However, if we place the AR-expressing tumor cells on laminin (the ECM found in tumors), these cells no longer die. We have determined that AR expression results in increased expression of a6b1 integrin, the receptor for laminin. Thus, AR-expressing tumor cells are likely to survive better when they remain adherent to the laminin-rich ECM that is present in the prostate gland. Survival under these conditions appears to depend on the ability of AR to enhance expression of the laminin receptor, a6b1 integrin; we are currently determining how AR regulates the expression of this integrin. Role of CD82 and integrin signaling in prostate cancer metastasis Death from prostate cancer is due to the development of metastatic disease, which is difficult to control. The mechanisms involved in progression to metastatic disease are not understood. One approach we are taking is to characterize genes that are specifically associated with metastatic prostate cancer. CD82/KAI1 is a metastasis suppressor gene whose expression is specifically lost in metastatic cancer, but not in primary tumors. Interestingly, CD82/KAI1 is known to associate with both integrins and RTKs. Our goal has been to determine how loss of CD82/KAI1 expression promotes metastasis by studying the role of CD82/KAI1 in integrin and RTK crosstalk. We have found that reexpression of CD82/KAI1 in metastatic tumor cells suppresses laminin-specific migration and invasion via suppression of both integrin- and ligand-induced activation of the RTK c-Met. Interestingly, c-Met is often overexpressed in metastatic prostate cancer. Thus, CD82/KAI1 normally acts to regulate signaling through c-Met such that upon CD82 loss in tumor cells, signaling through c-Met is increased, leading to increased invasion. We are currently determining the mechanism by which CD82/KAI1 down-regulates c-Met signaling. So far our investigations indicate that c-Met and CD82 do not directly interact, and CD82 may act to suppress c-Met signaling indirectly by dispersing the c-Met aggregates on metastatic tumor cells into monomers, thus blocking signaling. We are developing mutants of CD82 to determine which part of the CD82 molecule is required for suppression of c-Met activity. In addition, we have determined that reexpression of CD82 in tumor cells induces a physical association between CD82 and a related family member, CD9. Loss of CD9 prevents CD82 from suppressing c-Met. We are currently determining whether CD82/CD9 association with integrins is required to suppress c-Met. We have also initiated several mouse studies to demonstrate the importance of CD82 in regulating metastasis in vivo. Using orthotopic injection of wild-type or CD82-expressing metastatic prostate tumor cells directly into the prostate, we found that CD82 also suppresses metastasis in vivo. The ability of some prostate cancer cells to metastasize depends on activation of c-Met. Using mice that are able to specifically activate c-Met, we have been able to demonstrate that these tumor cells will only metastasize when c-Met is active. Under these conditions, reexpression of CD82 completely suppresses metastasis. In addition, we have generated mice in which CD82 expression is specifically lost in the epithelial cells of the prostate gland. These mice will be crossed to mice that develop only primary tumors to determine if the loss of CD82 is sufficient to induce prostate cancer metastasis. 40

VARI | 2008 External Collaborators Beatrice Knudsen, Fred Hutchinson Cancer Research Center, Seattle, Washington Valeri Vasioukin, Fred Hutchinson Cancer Research Center, Seattle, Washington Andries Zijlstra, Vanderbilt University, Nashville, Tennessee From left, standing: Bechtel, Rajah, Graf, Zarif, Holleywood, Spotts: seated: Schulz, Miranti, Guthrey, Tesfay, Saari, Lamb Recent Publications Edick, Mathew J., Lia Tesfay, Laura E. Lamb, Beatrice S. Knudsen, and Cindy K. Miranti. 2007. Inhibition of integrin-mediated crosstalk with epidermal growth factor receptor/Erk or Src signaling pathways in autophagic prostate epithelial cells induces caspase-independent death. Molecular Biology of the Cell 18(7): 2481–2490. Tolbert, W. David, Jennifer Daugherty, Chongfeng Gao, Qian Xie, Cindy Miranti, Ermanno Gherardi, George Vande Woude, and H. Eric Xu. 2007. A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proceedings of the National Academy of Sciences U.S.A. 104(37): 14592–14597. Wang, Xin, Jin Zhu, Ping Zhao, Yongjun Jiao, Ning Xu, Tessa Grabinski, Chao Liu, Cindy K. Miranti, Tao Fu, and Brian B. Cao. 2007. In vitro efficacy of immuno-chemotherapy with anti-EGFR human Fab-Taxol conjugate on A431 epidermoid carcinoma cells. Cancer Biology & Therapy 6(6): 980–987. 41

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