Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis

Recent studies have shown that lymphangiogenesis or the growth of lymphatic vessels at the periphery of tumors promotes tumor metastasis to lymph nodes. We show here that the fibronectin-binding integrin alpha4beta1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium. Tumors and lymphangiogenic growth factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGF-A, induce lymphatic vessel expression of integrin alpha4beta1. Integrin alpha4beta1 then promotes growth factor and tumor-induced lymphangiogenesis, as genetic loss of integrin alpha4beta1 expression in Tie2Cre+ alpha4(loxp/loxp) mice or genetic loss of alpha4 signaling in alpha4Y991A knock-in mice blocks growth factor and tumor-induced lymphangiogenesis, as well as tumor metastasis to lymph nodes. In addition, antagonists of integrin alpha4beta1 suppress lymphangiogenesis and tumor metastasis. Our studies show that integrin alpha4beta1 and the signals it transduces regulate the adhesion, migration, invasion, and survival of proliferating lymphatic endothelial cells. As suppression of alpha4beta1 expression, signal transduction, or function in tumor lymphatic endothelium not only inhibits tumor lymphangiogenesis but also prevents metastatic disease, these results show that integrin alpha4beta1-mediated tumor lymphangiogenesis promotes metastasis and is a useful target for the suppression of metastatic disease.