A critical role of VEGFR2 in lymphatic tumor metastasis

Abstract

Vascular endothelial growth factor receptor-2 (VEGFR2) transduces crucial signals for blood vessel growth but its role in the lymphatic system remains incompletely elucidated. By employing genetic mouse models targeting Vegfr2 in either pan-endothelial cells (ECs) or lymphatic endothelial cells (LECs), we examined roles of VEGFR2 in lymphangiogenesis and in tumor progression. VEGFR2 was differentially expressed in the murine lymphatic system and particularly marked in valves of collecting vessels. The pan-endothelial Vegfr2 deletion (Vegfr2iECKO) reduced the dermal lymphatic growth, and a significant decrease in lymphatic valves of pre-collectors was observed in mice with the LEC-specific attenuation of VEGFR2 (Vegfr2iLECKO). Furthermore, while the primary growth of subcutaneously implanted Lewis lung carcinoma was unaffected in the Vegfr2iLECKO mouse model, the tumor metastasis to sentinel lymph nodes was efficiently suppressed. In accordance, the tumor-associated lymphangiogenesis was decreased in the Vegfr2iLECKO mice compared with the control. Findings from this study imply that the lymphatic VEGFR2 regulates valve morphogenesis and promotes lymph node metastasis by regulating the tumor-associated lymphatic formation.