Role of Lymphangiogenesis in Orthotopic Prostatic Tumor-Environment on Regional and Systemic Metastasis

摘要

Pelvic lymph node metastasis in prostate cancer is associated with poor patient prognosis and clinical outcome(1). The extent of tumor-associated lymphangiogenesis augments lymphatic metastasis in many tumors types, although there have been limited studies in prostate cancer. Interestingly, we found that the metastatic potential of several prostate cancer xenografts is directly correlated with the expression of pro-lymphangiogenic factor, VEGF-C(2). To examine the contribution of tumor lymphangiogenesis to metastasis, we over- expressed lymphangiogenic growth factors in the non-metastatic LAPC-9 model expressing luciferase. An increase in intratumoral lymphangiogenesis, but not angiogenesis, enhanced both lymph node and lung metastasis. In converse experiments of down-regulation of lymphangiogenesis, we utilized soluble VEGFR- 3 and therapeutic antibody (a-mVEGFR-3, mF4-31C1, ImClone Inc.) to block VEGFC/ VEGFR-3 signaling in the more aggressive CWR22Rv-1 tumor. The expression of soluble VEGFR-3 in CWR22Rv-1 resulted in a significant reduction in intratumoral lymphatic vasculature, as well as metastasis to both regional lymph node and lung. These results indicate that tumor lymphangiogenesis is a key factor contributing to local regional lymph nodes and systemic metastasis in prostate cancer models. Hence, inhibiting tumor lymphangiogenesis may be a promising therapeutic strategy to suppress the deadly consequence of systemic metastasis of prostate cancer.