Abstract
Background Thespreadoftumorcellstolymphnodescommonlyoccursintumors and is an early event in metastasis tumor disease. Angiopoietin-1 is a major angiogenic andlymphangiogenicgrowthfactorincoloncarcinomaCT-26cellsatahypoxic condition. In this study, we investigated the inhibitory effects of recombinant canstatin and3-O-acetyloleanolicacid(3AOA) onangiopoietin-1-inducedlymphangiogenesis both in vitro and in vivo. Methods Toexaminetheinhibitoryeffectsofrecombinantcanstatinand3AOA on angiopoietin-1-inducedlymphangiognensis,weperformedproliferation,tube formation and migration assay using human lymphatic endothelial cells. The inhibitory effectsofrecombinantcanstatinand3AOAwerefurtherdeterminedinan angiopoietin-1-stimulatedinvivoMatrigelplugandaheterotropicCT-26colon carcinoma animal model. The anti-lymphangiogenic mechanisms ofrecombinant canstatin and 3AOA were investigated in lymphatic endothelial cells stimulated by angiopoietin-1 usingRT-PCR andwestern blotanalysis. Results Recombinant canstatin or 3AOA inhibited the proliferation, tube formation, andmigrationofangiopoietin-1-treatedhumanlymphaticendothelialcells. Recombinant canstatin inhibited lymphangiogenesis via suppression ofintegrin- dependent FAK signaling induced by angiopoietin-1/Tie-2 and/or VEGFR-3. 3AOA inhibitedtheactivationofsignalingfactorssuchasFAK,AKT,andERK1/2involvedin angiopoietin-1/Tie-2signalingpathway.Recombinantcanstatinand3AOAreducedthe developmentofnewlymphaticvesselsinangiopoietin-1-stimulatedMatrigelplug.Also recombinant canstatin and 3AOA inhibited the tumor growth and tumor-induced lymphangiogenesis in heterotropic CT-26 colon carcinoma animal model. Conclusions:Ourresultsindicatethatrecombinantcanstatinand 3AOAexhibitanti- lymphangiogeniceffects on angiopoietin-1-induced lymphangiogenesis. Ourfindings suggest that recombinant canstatin and 3AOA have a potential to inhibitcolon carcinoma. Currently,weinvestigatethecombinatoryeffectsofrecombinantcanstatinand3AOA. Legal entity responsible for the study Kyung Hee University Funding Basic Science Research Program through the National Research Foundation ofKorea(NRF),MinistryofEducation,ScienceandTechnology(NRF-2015R1D1A1A01059824) Disclosure All authors have declared no conflicts ofinterest.
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