Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in urinary bladder cancer

Abstract

High recurrence and metastasis is a hallmark of urinary bladder cancer, yet the relationship between lymphangiogenesis or lymphatic metastasis and urinary bladder cancer is unknown. Here, we identified a profound lymphangiogenesis in orthotopic urinary bladder cancer (OUBC) mice, a model generated by implantation of MBT-2 cell to urinary bladder. OUBC mice displayed massive infiltration of CD11b+/Gr-1+ tumor-associated macrophages (TAM) cells and dissemination of the OUBC cells in sentinel lymph nodes (SLN). Interestingly, CD11b+/Gr-1+ TAM are a source of lymphangiogenic growth factors such as vascular endothelial growth factor (VEGF)-C and VEGF-D (VEGF-C/D). The blockade of VEGF-C/D with soluble VEGF receptor-3 and the depletion of CD11b+/Gr-1+ TAM with clodronate liposome markedly inhibited OUBC-induced lymphangiogenesis and lymphatic metastasis to SLN. Our results indicate that VEGF-C/D are main factors for the OUBC-induced lymphangiogenesis and lymph node metastasis; moreover, CD11b+/Gr-1+ TAM could be responsible for the OUBC-induced lymphangiogenesis and lymph node metastasis by producing VEGF-C/D. These findings provide additional therapeutic target to lymphatic metastasis in the patients with urinary bladder cancer.