The most common site of prostate cancer metastasis is the bone with skeletal metastases identified at autopsy in up to 90% of patients dying from prostate cancer. The bone metastasis is initially sensitive to hormonal therapy, but with time the cancer eventually progresses to an androgen-independent state for which there is no effective treatment and has a medium survival of 9 months or less. It is critical that a solid understanding of the biology of prostate cancer skeletal metastatic process is developed to provide the basis for creating strategies to prevent or diminish their occurrence and associated complications. The intricate intercellular communication within the tumor microenvironment involves cell-cell, cell-insoluble extracellular matrices (ECMs), and cell-soluble factor mediated signaling processes, which support cancer cells growth and dissemination, therefore present an attractive target for therapeutic intervention. One critical step governing the process of bone metastasis is through selective attachment to organ』s lining endothelium and subsequently the organ』s ECM components though specific cell adhesion molecules (CAMs) utilized by prostate cancer cells. The goal of this project is to understand the molecular pathway of CAM-mediated tumor-stromal interaction in prostate cancer bone metastasis and design a reasonable therapeutic approach targeting the most vulnerable sites required for cell proliferation, survival, and intercellular communication. The hypothesis of this proposal is that a L1 cell adhesion molecule (L1CAM) expressed by both prostate cancer and bone marrow endothelial cells is responsible for site-specific tumor-endothelial interaction and tumor colonization in bone microenvironment. Interrupting L1CAM-mediated signaling can combat the lethal prostate cancer bone metastases. The proposal focuses on three themes. First, L1CAM-mediated reciprocal interaction confers tumor-stromal co-evolution in tumor microenvironment. Specific Aim 1 will address this theme by characterizing the possible L1CAM-responsive endothelial factors involved in prostate cancer cells homing to bone. Second, L1CAM functions not only as an adhesive molecule but also as a signal-transducing receptor regulating prostate cancer cell growth, migration, survival and its predilection for bone. Specific Aim 2 will assess this theme by defining the molecular pathway underlying L1CAM-mediated tumor-endothelial interaction in prostate cancer progression. Third, therapy for prostate bone metastasis can target not only the tumor cells but also the crosstalk between metastatic cells and organ-specific endothelium that enables tumor metastasis to organs. Specific Aim 3 will validate a L1CAM-based gene therapy approach based on the concept of targeting tumor-endothelium interaction on prostate cancer bone metastasis. Elucidation of the cellular and molecular mechanisms by which prostate cancer preferentially interacts with bone marrow endothelium is essential for the development of effective mechanism-based therapeutic intervention in prostate cancer metastasis.
