Tumor necrosis factor superfamily 15 promotes lymphatic metastasis via upregulation of vascular endothelial growth factor‐C in a mouse model of lung cancer

Lymphatic metastasis is facilitated by lymphangiogenic growth factor vascular endothelial growth factor‐C ( VEGFC ) that is secreted by some primary tumors. We previously identified tumor necrosis factor superfamily 15 ( TNFSF 15), a blood vascular endothelium‐derived cytokine, in lymphatic endothelial cells, as a key molecular modulator during lymphangiogenesis. However, the effect of TNFSF 15 on tumor lymphatic metastasis and the underlying molecular mechanisms remain unclear. We report here that TNFSF 15, which is known to inhibit primary tumor growth by suppressing angiogenesis, can promote lymphatic metastasis through facilitating lymphangiogenesis in tumors. Mice bearing tumors induced by A549 cells stably overexpressing TNFSF 15 exhibited a significant increase in densities of lymphatic vessels and a marked enhancement of A549 tumor cells in newly formed lymphatic vessels in the primary tumors as well as in lymph nodes. Treatment of A549 cells with TNFSF 15 results in upregulation of VEGFC expression, which can be inhibited by si RNA gene silencing of death domain‐containing receptor‐3 ( DR 3), a cell surface receptor for TNFSF 15. In addition, TNFSF 15/ DR 3 signaling pathways in A549 cells include activation of NF ‐κB during tumor lymphangiogenesis. Our data indicate that TNFSF 15, a cytokine mainly produced by blood endothelial cells, facilitates tumor lymphangiogenesis by upregulating VEGFC expression in A549 cells, contributing to lymphatic metastasis in tumor‐bearing mice. This finding also suggests that TNFSF 15 may have potential as an indicator for prognosis evaluation.