title: AIP1 Expression in Tumor Niche Suppresses Tumor Progression and Metastasis.
abstract: Studies from tumor cells suggest that tumor-suppressor AIP1 inhibits epithelial-mesenchymal transition (EMT). However, the role of AIP1 in the tumor microenvironment has not been examined. We show that a global or vascular endothelial cell (EC)-specific deletion of the AIP1 gene in mice augments tumor growth and metastasis in melanoma and breast cancer models. AIP1-deficient vascular environment not only enhances tumor neovascularization and increases premetastatic niche formation, but also secretes tumor EMT-promoting factors. These effects from AIP1 loss are associated with increased VEGFR2 signaling in the vascular EC and could be abrogated by systemic administration of VEGFR2 kinase inhibitors. Mechanistically, AIP1 blocks VEGFR2-dependent signaling by directly binding to the phosphotyrosine residues within the activation loop of VEGFR2. Our data reveal that AIP1, by inhibiting VEGFR2-dependent signaling in tumor niche, suppresses tumor EMT switch, tumor angiogenesis, and tumor premetastatic niche formation to limit tumor growth and metastasis.
authors.affiliation: The First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Public Health, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology, Vascular Biology Program/Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Yin
authors.affiliation: Department of Pathology, Vascular Biology Program/Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Huanjiao Jenny
authors.initials: HJ
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Pathology, Vascular Biology Program/Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen University, Guangzhou, China. Department of Pathology, Vascular Biology Program/Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. wang.min@yale.edu.
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D051528:Guanylate Kinases; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D047428:Protein Kinase Inhibitors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051528:Guanylate Kinases; C485777:MAGI2 protein, human