Abstract
Previously, we reported that high-fat-diet (HFD)-induced obesity stimulates melanoma progression in the B16F10 allograft model. In this study, we examined whether oleuropein (OL), the most abundant phenolic compound in olives, inhibits HFD-induced melanoma progression. Four-week-old male C57BL/6N mice were fed a HFD-diet with or without OL. After 16 weeks of feeding, B16F10-luc cells were subcutaneously injected and the primary tumor was resected 3 weeks later. OL suppressed HFD-induced solid tumor growth. In the tumor tissues, OL reduced HFD-induced expression of angiogenesis (CD31, VE-cadherin, VEGF-A, and VEGFR2), lymphangiogenesis (LYVE-1, VEGF-C, VEGF-D, and VEGFR3), and hypoxia (HIF-1α and GLUT-1) markers as well as HFD-induced increases in lipid vacuoles and M2 macrophages (MΦs). All animals were euthanized 2.5 weeks after tumor resection. OL suppressed HFD-induced increases in lymph node (LN) metastasis; expression of VEGF-A, VEGF-C, and VEGF-D in the LN; and M2-MΦs and the size of adipocytes in adipose tissues surrounding LNs. Co-culture results revealed that the crosstalk between B16F10s, M2-MΦs, and differentiated 3T3-L1 cells under hypoxic conditions increased the secretion of VEGF-A and -D, which stimulated tube formation and migration of endothelial cells (HUVECs) and lymphatic endothelial cells (LEC), respectively. Additionally, OL directly inhibited the differentiation of 3T3-L1 preadipocytes and tube formation by HUVECs and LECs. The overall results indicated that dietary OL inhibits lipid and M2-MΦ accumulation in HFD-fed mice, which contributes to decreases in VEGF secretion, thereby leading to inhibition of angiogenesis and lymphangiogenesis.
Highlights
Epidemiological studies indicate that overweight and obesity are associated with increased risks of developing several cancers, including melanoma [1,2,3]
Co-culture results revealed that the crosstalk between B16F10s, M2-MΦs, and differentiated 3T3-L1 cells under hypoxic conditions increased the secretion of Vascular endothelial growth factor (VEGF)-A and -D, which stimulated tube formation and migration of endothelial cells (HUVECs) and lymphatic endothelial cells (LEC), respectively
Our results indicated that the crosstalk between adipocytes, M2-MΦs and B16F10 melanoma cells under hypoxic conditions is important for angiogenesis and lymphangiogenesis, and is blocked by OL
Summary
Epidemiological studies indicate that overweight and obesity are associated with increased risks of developing several cancers, including melanoma [1,2,3]. Our previous report demonstrated that highfat diet (HFD)-induced obesity stimulates tumor growth and lymph node (LN) metastasis of B16F10 melanoma cells in C57BL/6 mice [5]. Tumor angiogenesis is a major feature of tumor growth and metastasis, and includes endothelial cell proliferation and migration, tube formation, degradation of extracellular matrix, and sprouting of new capillaries (reviewed in [11]). Lymphangiogenesis requires the coordination of several cellular events, including proliferation, sprouting, migration and tube formation, similar to events related to angiogenesis (reviewed in [10]). VEGFs bind to VEGF receptor (VEGFR)s on neighboring endothelial cells and promote the growth and development of new blood vessels [15]
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