High‐fat diet‐induced obesity increases lymphangiogenesis and lymph node metastasis in the B16F10 melanoma allograft model: Roles of adipocytes and M2‐macrophages

To examine the effects of high‐fat diet (HFD) on melanoma progression, HFD‐fed C57BL/6N mice were subcutaneously injected with syngeneic B16F10 melanoma cells. At 3 weeks post‐injection, the tumors were resected; the mice were then sacrificed at 2 weeks post‐resection. HFD stimulated melanoma growth and lymph node (LN) metastasis as well as tumor and LN lymphangiogenesis. Lipid vacuoles in the tumor and M2‐macrophage (MΦ)s in the adipose and tumor tissues were increased in HFD‐fed mice. CCL19 and CCL21 contents were higher in LNs than in tumors. HFD increased both CCL19 and CCL21 levels in LNs and CCR7 in tumors. Adipose tissue‐conditioned media (CM) from HFD‐fed mice enhanced lymphangiogenesis, and mature adipocyte (MA)/M2‐MΦ co‐culture CM markedly stimulated the tube formation of lymphatic endothelial cell (LEC)s and B16F10 migration. Monocyte migration was moderately stimulated by B16F10 or MA CM, but tremendously stimulated by B16F10/M2‐MΦ co‐culture CM, which was enhanced by MA/B16F10/M2‐MΦ co‐culture CM. The co‐culture results revealed that MAs increased CCL2, M‐CSF and CCR7 mRNAs in B16F10s; vascular endothelial growth factor (VEGF)‐D mRNA in M2‐MΦs; and CCL19, CCL21 and VEGF receptor (VEGFR)3 mRNA in LECs. M2‐MΦs increased CCL2, M‐CSF and VEGF‐A mRNAs in B16F10s, whereas B16F10s increased VEGF‐C mRNAs in M2‐MΦs and VEGFR3 mRNA in LECs. These results indicate that in HFD‐fed mice, MA‐induced CCL2 and M‐CSF in tumor cells increase M2‐MΦs in tumor; the crosstalk between tumor cells and M2‐MΦs further increases cytokines and angiogenic and lymphangiogenic factors. Additionally, MA‐stimulated CCL19, CCL21/CCR7 axis contributes to increased LN metastasis in HFD‐fed mice. What's new? Human studies indicate that there may be a link between obesity and melanoma. Evidence also suggests that chemokines, such as those released by adipocytes, play a pivotal role in metastasis of melanoma and other cancers. In this study, the authors found that obesity caused by a high‐fat diet stimulates melanoma metastasis in vivo. Using mouse and in vitro co‐culture models, the study also demonstrates that increased adipocytes enhance lymphangiogenesis and lymph‐node metastasis in obese animals, in part via interaction with M2‐macrophages.