Inflammatory cytokines induce vascular endothelial growth factor-C expression in melanoma-associated macrophages and stimulate melanoma lymph node metastasis

Lymph node colonization by tumor cells is one of the key determinants of melanoma staging and prognosis, and tumor-associated macrophages (TAMs) are the predominant type of inflammatory cell in the tumor environment which secretes vascular endothelial growth factor (VEGF)-C, the most potent lymphangiogenic growth factor. In the present study, to elucidate the mechanism involved in VEGF-C expression in TAMs, murine peritoneal macrophages were co-cultivated with syngeneic B16 melanoma cells to mimic the reciprocal interactions between tumor cells and macrophages found in spontaneous tumors. In the present study, upon contact with tumor cells, macrophages were found to express a higher level of VEGF-C which was associated with an increase in the expression of IL-1β and TNF-α and their receptors. Antibodies against the IL-1β and TNF-α receptors were added to media that had been conditioned by the macrophage-tumor cell co-cultures and inhibition of VEGF-C was observed in macrophages co-cultivated with the tumor cells. Furthermore, when IL-1β and TNF-α were used at a non-toxic level, they enhanced peritoneal lymph node colonization by melanoma cells. Thus, in the present study, macrophagic IL-1β and TNF-α were observed to promote VEGF-C expression in TAMs, as well as melanoma lymph node metastasis, suggesting that inhibiting the signaling between tumor cells and TAMs may be required to inhibit lymphangiogenesis and lymph node metastasis.