title: Antitumor and Antimetastatic Activity of Synthetic Hydroxystilbenes Through Inhibition of Lymphangiogenesis and M2 Macrophage Differentiation of Tumor-associated Macrophages.
abstract: An increase in tumor-associated macrophages (TAMs) around the tumor microenvironment has been closely associated with a poor prognosis in patients with cancer, and M2 TAMs promote tumor growth and tumor metastasis by stimulating angiogenesis or lymphangiogenesis in tumors. We herein examined the effects of nine synthetic hydroxystilbenes on M2 macrophage activation and differentiation, and three selected dihydroxystilbenes on vascular endothelial cell growth factor (VEGF)-C-induced tube formation in human lymphatic endothelial cells (HLECs) (in vitro). We also investigated the antitumor and antimetastatic effects of three synthetic dihydroxystilbenes in LM8-bearing mice in vivo. The three selected synthetic stilbenes (at concentrations of 5, 10, 25, and 50 μM) inhibited the production of interleukin-10 and monocyte chemoattractant protein-1 in M2 macrophages, but promoted that of transforming growth factor-β1. The three dihydroxystilbenes (at concentrations of 10-50 μM) inhibited the phosphorylation of signal transducer and activator of transcript 3 without affecting its expression in the differentiation of M2 macrophages. Furthermore, the 2,3- and 4,4'-dihydroxystilbene inhibited VEGF-C-induced lymphangiogenesis in HLECs. Both 2,3- and 4,4'-dihydroxystilbene (at 10 and 25 mg/kg, twice daily) inhibited tumor growth and metastasis to the lung in mice. These results suggested that the antitumor and antimetastatic effects of 2,3- and 4,4'-dihydroxystilbene were partly due to anti-lymphangiogenesis, and the regulation of M2 macrophage activation and differentiation.
authors.affiliation: Division of Biochemical Pharmacology, Department of Basic Medical Research, Graduate School of Medicine, Ehime University, Shitsukawa, Toon City, Ehime, Japan yokim@m.ehime-u.ac.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Division of Biochemical Pharmacology, Department of Basic Medical Research, Graduate School of Medicine, Ehime University, Shitsukawa, Toon City, Ehime, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Sumiyoshi
authors.affiliation: Department of Pharmacognosy, Osaka University of Pharmaceutical Sciences, Takatsuki City, Osaka, Japan.
authors.forename: Kimiye
authors.initials: K
authors.lastname: Baba
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D042583:Lymphangiogenesis / Q000187:drug effects*; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D010641:Phenotype; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000138:chemical synthesis / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D059016:Tumor Microenvironment; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508609:IL10 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D042582:Vascular Endothelial Growth Factor C; D016753:Interleukin-10
keywords: Antitumor; M2 macrophages; anti-lymphangiogenesis; antimetastasis; dihydroxystilbenes