Dietary Oleuropein (Ol) Improves High-Fat Diet-Induced Metabolic Stress And Suppresses Solid Tumor Growth And Lymph Node (Ln) Metastasis In The B16f10 Melanoma Allograft Model

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Epidemiological studies indicate that obesity-associated metabolic stress increases the risk of developing several cancers. We previously reported that a high-fat diet (HFD)-induced obesity stimulates tumor growth and metastasis of B16F10 melanoma cancer cells in C57BL/6 mice. OL, the most abundant phenolic compound in olives, was reported to exert several physiological activities, including antioxidative, anticancer, and antimicrobial activities. In the present study, we examined whether OL inhibits HFD-induced melanoma progression in the B16F10 allograft model. Four-week old, male C57BL/6N mice were fed a diet [control diet (10 kcal% fat), HFD (60 kcal% fat), HFD + 0.02% OL, or HFD + 0.04% OL]. Twelve weeks after the initiation of feeding, fasting blood glucose, plasma insulin, and HOMA-IR were increased in HFD-fed mice, which was suppressed by dietary OL. Dual-energy X-ray absorptiometry results revealed that the proportion of lean body mass was decreased, whereas that of fat mass was increased in HFD-fed mice, and these changes were suppressed by dietary OL. After 16 weeks of feeding, B16F10-luc cells were subcutaneously injected into the animals’ left flank; bioluminescence imaging was conducted; and the primary tumor was resected 3 weeks later. OL suppressed HFD-induced solid tumor growth; HFD-induced increases in the expression of Ki67, cyclin D1, VEGF-A, VEGF-C, VEGF-D, CD31 (platelet endothelial cell adhesion molecule-1) and LYVE (lymphatic vessel endothelial receptor)-1; and HFD-induced decreases in TUNEL-positive apoptotic cells and cleaved PARP levels in the tumor tissues. OL also suppressed HFD-induced changes in the levels of many cytokines/chemokines in tumor tissues. All animals were killed 3 weeks after the tumor resection. OL suppressed HFD-induced increases in the size of LN; LN metastasis; and expression of VEGF-A and VEGF-C in the LN. OL suppresses HFD-induced increases in the size of adipocytes and accumulation of F4/80+ macrophages in adipose tissues surrounding the LN. In vitro culture results revealed that OL inhibited lipid accumulation in 3T3-L1 preadipocytes and the migration and viability of B16F10 cells. The present results demonstrated that dietary OL suppresses tumor growth and LN metastasis in HFD-fed mice. These effects are probably mediated, at least in part, via the inhibition of lipid accumulation, thereby reducing obesity-associated metabolic stress. Additionally, in vitro results indicate that OL may directly inhibit melanoma cell growth and migration, which may be one of the mechanisms by which dietary OL suppress melanoma progression in these mice. Citation Format: Hyerim Song, Jae In Jung, Gyoo Taik Kwon, So Young Park, Han Jin Cho, Jung Han Yoon Park. Dietary oleuropein (OL) improves high-fat diet-induced metabolic stress and suppresses solid tumor growth and lymph node (LN) metastasis in the B16F10 melanoma allograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 911. doi:10.1158/1538-7445.AM2015-911