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Updated: Oct 14, 2025
Isolation and Culture Expansion of Tumor-specific Endothelial Cells
Published on: October 14, 2015
Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization
Zhiyong Xu1,2, Chunyi Guo1, Qiaoli Ye1
1Department of Pathology and Pathophysiology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
SHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvascular density in multiple mouse tumor models. Shp2 deletion also leads to tumor vascular normalization, indicated by increased pericyte coverage and vessel perfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration, and tubulogenesis through downregulating the expression of proangiogenic SRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelial function in SHP2-knockdown cells and tumor growth, angiogenesis, and vascular abnormalization in Shp2-deleted mice. SHP2 stabilizes apoptosis signal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated by c-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is a promising anti-angiogenic target for cancer therapy.
Insights
SHP2 protein is crucial for tumor blood vessel formation. Inhibiting SHP2 in endothelial cells reduces tumor growth and normalizes blood vessels, suggesting SHP2 as a potential anti-angiogenic cancer therapy target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- SHP2 (PTPN11) is a key regulator of receptor tyrosine kinase signaling pathways.
- Its role in endothelial cell function is established, but its specific involvement in tumor angiogenesis remains underexplored.
- Genetic studies are needed to elucidate SHP2's function in tumor-associated endothelial cells.
Purpose of the Study:
- To investigate the role of SHP2 in tumor angiogenesis using genetic approaches.
- To determine if SHP2 inhibition can serve as an anti-angiogenic strategy in cancer therapy.
- To identify downstream effectors and pathways regulated by SHP2 in tumor endothelial cells.
Main Methods:
- Utilized mouse tumor models with Shp2 deletion in endothelial cells.
- Administered pharmacological SHP2 inhibitors.
- Assessed tumor growth, microvascular density, pericyte coverage, and vessel perfusion.
- Analyzed endothelial cell proliferation, migration, and tubulogenesis in vitro.
- Investigated the expression of SOX7 and ASK1 pathways.
Main Results:
- SHP2 is activated in tumor endothelia and its deletion/inhibition significantly reduces tumor growth and microvascular density.
- Shp2 deletion promotes tumor vascular normalization, evidenced by enhanced pericyte coverage and perfusion.
- SHP2 deficiency impairs endothelial cell functions by downregulating SOX7, a proangiogenic factor. Re-expression of SOX7 rescues these defects.
- SHP2 stabilizes ASK1, which mediates c-Jun-dependent regulation of SOX7.
Conclusions:
- SHP2 plays a critical role in tumor angiogenesis by regulating endothelial cell proliferation, migration, and vascular structure.
- Targeting SHP2 in tumor-associated endothelial cells offers a promising therapeutic strategy for reducing tumor growth and vascularization.
- The SHP2-ASK1-c-Jun-SOX7 axis is a key pathway in SHP2-mediated tumor angiogenesis.
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