title: Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling.
abstract: Foretinib, a multiple kinase inhibitor undergoing clinical trials, could suppress the activity of hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, Foretinib may inhibit two critical lymphangiogenic signaling receptors VEGFR-3 and TIE-2. However, the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo is still unknown. We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations. However, Foretinib only reduced the proliferation of pancreatic cancer cells at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells. Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs. In xenograft animal study, Foretinib suppressed tumor growth by inhibiting proliferation, angiogenesis and lymphangiogenesis. Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study. Collectively, we suggested that Foretinib simultaneously inhibits cancer cells and LECs to reduce pancreatic tumor growth in vivo and demonstrated for the first time that Foretinib suppresses angiogenesis and lymphangiogenesis by blocking VEGFR-2/3 and TIE-2 signaling.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.
authors.forename: Hsiu-Mei
authors.initials: HM
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
mesh_terms: D042702:Angiopoietin-2 / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D042702:Angiopoietin-2; D000813:Anilides; C544831:GSK 1363089; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D019859:Proto-Oncogene Proteins c-met; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: LYVE-1; TIE-2; c-MET; foretinib; vascular growth factor receptor