Role of interleukin-17 in lymphangiogenesis in non-small-cell lung cancer: Enhanced production of vascular endothelial growth factor C in non-small-cell lung carcinoma cells

Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in inflammation and cancer. Recently, we found that increased IL-17-producing cells correlate with poor survival and increased lymphangiogenesis in non-small-cell lung cancer (NSCLC), but the mechanism is unknown. Here, we show that IL-17 promotes lymphangiogenesis via inducing vascular endothelial growth factor-C (VEGF-C) production by lung cancer cells. We found that IL-17 receptor (IL-17R) is expressed on the surface of Lewis lung carcinoma (LLC) cells but not on lymphatic endothelial cells (LEC). Moreover, LEC chemotaxis and tube formation (measures of net lymphangiogenic potential) were increased by conditioned medium from recombinant mouse IL-17 (rmIL-17)-stimulated LLC but not by rmIL-17. Interleukin-17 increased production of VEGF-C in lung cancer cell lines. The enhanced chemotaxis and endothelial cord formation in the presence of LLC/rmIL-17 was inhibited by addition of recombinant mouse VEGF R3/Fc chimera. Treatment of the A549 cells with rIL-17 significantly increased VEGF-C expression, which was extracellular signal-regulated protein kinase 1/2 (ERK 1/2) dependent. Importantly, we found significant correlations between IL-17 expression, VEGF-C expression and lymphatic vascular density (LVD) in NSCLC. We conclude that IL-17 is involved in lymphangiogenesis in NSCLC by enhancing production of VEGF-C, and IL-17 may be an important target for the treatment of NSCLC. (Cancer Sci 2010; 101: 2384-2390).