Resveratrol Prevents Tumor Growth and Metastasis by Inhibiting Lymphangiogenesis and M2 Macrophage Activation and Differentiation in Tumor-associated Macrophages

• Published in: Nutrition and cancer Vol. 68; no. 4; pp. 667 - 678
• Main Authors: Kimura, Yoshiyuki, Sumiyoshi, Maho
• Format: Journal Article
• Language: English
• Published: United States Routledge 18.05.2016; Taylor & Francis Ltd
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Chemokine CCL2 - metabolism; Growth factors; Humans; Interleukin-10 - metabolism; Lymphangiogenesis - drug effects; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Metastasis; Mice, Inbred C3H; Osteosarcoma - drug therapy; Osteosarcoma - pathology; Polyphenols; STAT3 Transcription Factor - metabolism; Stilbenes - pharmacology; Transforming Growth Factor beta1 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0163-5581; 1532-7914
• DOI: 10.1080/01635581.2016.1158295

Antitumor and antimetastatic effects of resveratrol on tumor-induced lymphangiogenesis through the regulation of M2 macrophages in tumor-associated macrophages currently remain unknown. Therefore, we herein examined the effects of resveratrol on M2 macrophage activation and differentiation, and those of resveratrol-treated condition medium (CM) in M2 macrophages on vascular endothelial cell growth factor (VEGF)-C-induced migration, invasion, and tube formation by human lymphatic endothelial cells (HLECs). Resveratrol (50 μM or 5-50 μM) inhibited the production of interleukin-10 and monocyte chemoattractant protein-1 in M2 macrophages, whereas it promoted that of transforming growth factor-β 1 . Resveratrol (25 and 50 μM) inhibited the phosphorylation of signal transducer and activator of transcript 3 without affecting its expression in the differentiation process of M2 macrophages. Furthermore, resveratrol-treated CM of M2 macrophages inhibited VEGF-C-induced HLEC migration, invasion, and lymphangiogenesis. Resveratrol (25 mg/kg, twice daily) inhibited tumor growth and metastasis to the lung and also reduced the area of lymphatic endothelial cells in tumors (in vivo). These results suggest that the antitumor and antimetastatic effects of resveratrol were partly due to antilymphangiogenesis through the regulation of M2 macrophage activation and differentiation.