Introduction: Foretinib is a multiple kinase inhibitor undergoing different phase clinical trials and exhibits potent inhibitory effect on hepatocyte growth factor (HGF) receptor c-MET and vascular endothelialgrowth factor receptor-2 (VEGFR-2) and TIE-2. Aims: In this study, we investigated the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo. Materials & methods: MTT assay was used to evaluate cell proliferation. Westrn blotting was done to study apoptotic cell death and the activation status of different signaling pathways. Xenograft and orthotopic animal models were used to investigate the anti-cancer effect of Foretinib on pancreatic cancer. Immunohistochemical satining was performed to assess the parameters of cell proliferation, angiogenesis and lymphangiogenesis. Results: Foretinib inhibited basal- and HGF-induced c-MET activity at low concentrations. However, Foretinib only suppressed the proliferation of pancreatic cancer cells at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells. Foretinib inhibited VEGFA, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs and triggered apoptotic cell death of LECs. At molecular level, Foretinib attenuated growth factor-induced VEGFR-2, VEGFR-3 and TIE-2 activation in LECs. In xenograft animal study, Foretinib suppressed tumor growth and reduced proliferation, angiogenesis and lymphangiogenesis. In orthotopic animal study, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect on experimental animals. Conclusion: Our results suggested that Foretinib simultaneously targets cancer cells and LECs to inhibit pancreatic tumor growth and demonstrated for the first time that Foretinib suppresses angiogenesis and lymphangiogenesis by blocking multiple signaling.
