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AIP1 Expression in Tumor Niche Suppresses Tumor Progression and Metastasis
Weidong Ji1, Yonghao Li2, Yun He3
1The First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen University, Guangzhou, China.
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.
Insights
The tumor suppressor AIP1 inhibits tumor growth and metastasis by blocking VEGFR2 signaling in the tumor microenvironment. Loss of AIP1 in vascular cells promotes tumor angiogenesis and EMT, increasing cancer spread.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor-suppressor AIP1 is known to inhibit epithelial-mesenchymal transition (EMT) in tumor cells.
- The role of AIP1 within the tumor microenvironment, particularly in vascular endothelial cells (ECs), remains unexplored.
Purpose of the Study:
- To investigate the function of AIP1 in the tumor microenvironment.
- To elucidate the mechanisms by which AIP1 influences tumor growth, angiogenesis, and metastasis.
Main Methods:
- Utilized mouse models with global or EC-specific AIP1 gene deletion.
- Analyzed tumor growth, neovascularization, and premetastatic niche formation in melanoma and breast cancer models.
- Investigated VEGFR2 signaling pathways and AIP1's direct interaction with VEGFR2.
Main Results:
- AIP1 deficiency in the vascular environment significantly augmented tumor growth and metastasis.
- AIP1-deficient ECs enhanced tumor neovascularization and premetastatic niche formation.
- AIP1 loss increased VEGFR2 signaling, which was reversed by VEGFR2 kinase inhibitors; AIP1 directly binds to VEGFR2's activation loop.
Conclusions:
- AIP1 suppresses tumor growth and metastasis by inhibiting VEGFR2-dependent signaling in the tumor niche.
- AIP1's function in the tumor microenvironment is critical for preventing EMT, angiogenesis, and premetastatic niche formation.
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