Dietary oleuropein inhibits tumor angiogenesis and lymphangiogenesis in the B16F10 melanoma allograft model: a mechanism for the suppression of high-fat diet-induced solid tumor growth and lymph node metastasis

// Hyerim Song 1, * , Do Young Lim 2, * , Jae In Jung 3 , Han Jin Cho 1, 4 , So Young Park 1, 5 , Gyoo Taik Kwon 1, 5, 6 , Young-Hee Kang 1 , Ki Won Lee 4, 5, 7 , Myung-Sook Choi 8 , Jung Han Yoon Park 1, 5, 7 1 Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea 2 The Hormel Institute, University of Minnesota, Austin, MN 55912, USA 3 Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon 24341, Republic of Korea 4 WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Republic of Korea 5 Advanced Institutes of Convergence Technology, Seoul National University, Suwon 16229, Republic of Korea 6 Berry and Biofood Research Institute, Jeonbuk 56417, Republic of Korea 7 Research Institute of Agriculture and Life Science, Seoul National University, Seoul 08826, Republic of Korea 8 Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea * These authors contributed equally to this work Correspondence to: Jung Han Yoon Park, email: junedong9@snu.ac.kr Keywords: oleuropein, melanoma, metastasis, angiogenesis, lymphangiogenesis Received: September 09, 2016      Accepted: March 20, 2017      Published: March 31, 2017 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.