974. Adeno-Associated Viral (AAV)-Mediated Gene Transfer of Soluble Vascular Endothelial Growth Factor Receptor 3 (sVEGFR3) Inhibits Development of Lymph Node Metastases

The metastatic spread of tumor cells represents a critical point in tumor progression. The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival in many types of cancer. Production of the lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), has been detected in tumors and the significance of VEGF-C mediated lymphangiogenesis for tumors has been demonstrated. VEGF-C stimulates tumor lymphangiogenesis and metastasis to regional lymph nodes by binding to VEGF receptor 3 (VEGFR3). A number of studies have demonstrated that blocking VEGFR3 signaling suppresses tumor lymphangiogenesis and lymph node metastasis. In this study, we investigated whether AAV-mediated gene delivery of a soluble VEGFR3 fusion protein, sVEGFR3-Fc, inhibits development of lymph node metastases in prostate (PC-3mlg2) and melanoma (A375mln1) tumor models. Tumor cell lines were established from lymph node metastases of mice bearing PC-3 and A375 subcutaneous tumors, respectively. These tumor cell lines were transduced with the luciferase gene enabling the detection of lymphatic and systemic metastases by luminescence imaging. A single injection of AAV-sVEGFR3-Fc inhibited tumor cell metastasis to the regional lymph nodes. The inhibition was approximately 70% in PC-3mlg2 and A375mln1 models, as evident by the reduced number of tumor-bearing lymph nodes when compared with the animals injected with an AAV null vector. We are currently performing dose response studies in both tumor models to determine the optimum VEGFR3 serum levels required for efficient block of lymphogenic metastasis.These findings demonstrate that AAV-mediated gene delivery of sVEGFR3-Fc inhibits development of lymph node metastases in tumor bearing animals. This study suggests that gene therapy using AAV-mediated sVEGFR3 gene transfer might be a feasible strategy for the prevention or treatment of lymphogenous metastasis.