β-Caryophyllene potently inhibits solid tumor growth and lymph node metastasis of B16F10 melanoma cells in high-fat diet-induced obese C57BL/6N mice

• Published in: Carcinogenesis (New York) 2015-09, Vol.36 (9), p.1028-1039
• Main Authors: Jung, Jae In, Kim, Eun Ji, Kwon, Gyoo Taik, Jung, Yoo Jin, Park, Taesung, Kim, Yongkang, Yu, Rina, Choi, Myung-Sook, Chun, Hyang Sook, Kwon, Seung-Hae, Her, Song, Lee, Ki Won, Park, Jung Han Yoon
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocytes - metabolism; Animals; Antineoplastic Agents - pharmacology; Body Weight; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemokine CCL19 - antagonists & inhibitors; Chemokine CCL19 - metabolism; Chemokine CCL2 - metabolism; Chemokine CCL2 - secretion; Chemokine CCL21 - antagonists & inhibitors; Chemokine CCL21 - metabolism; Diet, High-Fat - adverse effects; Dietary Fats; Lectins, C-Type - metabolism; Lymph Nodes - pathology; Lymphatic Metastasis; Macrophages - cytology; Male; Mannose-Binding Lectins - metabolism; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - prevention & control; Obesity - pathology; Random Allocation; Receptors, CCR7 - antagonists & inhibitors; Receptors, CCR7 - biosynthesis; Receptors, Cell Surface - metabolism; Sesquiterpenes - pharmacology; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Subcutaneous Fat - cytology; Subcutaneous Fat - pathology; Vacuoles - pathology; Weight Gain - drug effects
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgv076

We reported previously that high-fat diet (HFD) feeding stimulated solid tumor growth and lymph node (LN) metastasis in C57BL/6N mice injected with B16F10 melanoma cells. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in many essential oils and has been shown to exert anti-inflammatory activities. To examine whether BCP inhibits HFD-induced melanoma progression, 4-weeks old, male C57BL/6N mice were fed a control diet (CD, 10 kcal% fat) or HFD (60 kcal% fat + 0, 0.15 or 0.3% BCP) for the entire experimental period. After 16 weeks of feeding, B16F10s were subcutaneously injected into mice. Three weeks later, tumors were resected, and mice were killed 2 weeks post-resection. Although HFD feeding increased body weight gain, fasting blood glucose levels, solid tumor growth, LN metastasis, tumor cell proliferation, angiogenesis and lymphangiogenesis, it decreased apoptotic cells, all of which were suppressed by dietary BCP. HFD feeding increased the number of lipid vacuoles and F4/80+ macrophage (MΦ) and macrophage mannose receptor (MMR)+ M2-MΦs in tumor tissues and adipose tissues surrounding the LN, which was suppressed by BCP. HFD feeding increased the levels of CCL19 and CCL21 in the LN and the expression of CCR7 in the tumor; these changes were blocked by dietary BCP. In vitro culture results revealed that BCP inhibited lipid accumulation in 3T3-L1 preadipocytes; monocyte migration and monocyte chemoattractant protein-1 secretion by B16F10s, adipocytes and M2-MΦs; angiogenesis and lymphangiogenesis. The suppression of adipocyte and M2-cell accumulation and the inhibition of CCL19/21-CCR7 axis may be a part of mechanisms for the BCP suppression of HFD-stimulated melanoma progression.