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 (M)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-M 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-M phi co-culture CM, which was enhanced by MA/B16F10/M2-M phi 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-M phi s; and CCL19, CCL21 and VEGF receptor (VEGFR)3 mRNA in LECs. M2-M phi s increased CCL2, M-CSF and VEGF-A mRNAs in B16F10s, whereas B16F10s increased VEGF-C mRNAs in M2-M phi s and VEGFR3 mRNA in LECs. These results indicate that in HFD-fed mice, MA-induced CCL2 and M-CSF in tumor cells increase M2-M phi s in tumor; the crosstalk between tumor cells and M2-M phi s 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.