Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization.

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.

• Authors: Zhiyong Xu, Chunyi Guo, Qiaoli Ye, Yueli Shi, Yihui Sun, Jie Zhang, Jiaqi Huang, Yizhou Huang, Chunlai Zeng, Xue Zhang, Yuehai Ke, Hongqiang Cheng
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6310 (11 02 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34728626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• SOX7 protein, human
• SOXF Transcription Factors
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, mouse

Topics

• Animals
• Cell Proliferation
• Cells, Cultured
• Disease Models, Animal
• Endothelial Cells (metabolism, pathology)
• Humans
• Mice
• Mice, Knockout
• Neoplasms (genetics, metabolism, pathology)
• Neovascularization, Pathologic (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (deficiency, genetics, metabolism)
• SOXF Transcription Factors (metabolism)
• Signal Transduction