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
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Hyerim Song1,*, Do Young Lim2,*, Jae In Jung3, Han Jin Cho1,4, So Young Park1,5, Gyoo Taik Kwon1,5,6, Young-Hee Kang1, Ki Won Lee4,5,7, Myung-Sook Choi8, Jung Han Yoon Park1,5,7
1Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
2The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
3Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon 24341, Republic of Korea
4WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Republic of Korea
5Advanced Institutes of Convergence Technology, Seoul National University, Suwon 16229, Republic of Korea
6Berry and Biofood Research Institute, Jeonbuk 56417, Republic of Korea
7Research Institute of Agriculture and Life Science, Seoul National University, Seoul 08826, Republic of Korea
8Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea
*These authors contributed equally to this work
Jung Han Yoon Park, email: firstname.lastname@example.org
Keywords: oleuropein, melanoma, metastasis, angiogenesis, lymphangiogenesis
Received: September 09, 2016 Accepted: March 20, 2017 Published: March 31, 2017
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.
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