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Cancer Res. 2015 Sep 1;75(17):3492-504. doi: 10.1158/0008-5472.CAN-15-0088. Epub 2015 Jul 2.

AIP1 Expression in Tumor Niche Suppresses Tumor Progression and Metastasis.

Author information

1
The First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen University, Guangzhou, China.
2
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
3
School of Public Health, Sun Yat-sen University, Guangzhou, China.
4
Department of Pathology, Vascular Biology Program/Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
6
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.

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.

PMID:
26139244
PMCID:
PMC4558200
DOI:
10.1158/0008-5472.CAN-15-0088
[Indexed for MEDLINE]
Free PMC Article

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