Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization

Zhiyong Xu, Chunyi Guo, Qiaoli Ye, Yueli Shi, Yihui Sun, Jie Zhang, Jiaqi Huang, Yizhou Huang, Chunlai Zeng, Xue Zhang, Yuehai Ke () and Hongqiang Cheng ()
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Zhiyong Xu: Zhejiang University School of Medicine
Chunyi Guo: Zhejiang University School of Medicine
Qiaoli Ye: Zhejiang University School of Medicine
Yueli Shi: Zhejiang University School of Medicine
Yihui Sun: Zhejiang University School of Medicine
Jie Zhang: Zhejiang University School of Medicine
Jiaqi Huang: Zhejiang University School of Medicine
Yizhou Huang: Zhejiang University School of Medicine
Chunlai Zeng: Lishui Hospital of Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital
Xue Zhang: Zhejiang University School of Medicine
Yuehai Ke: Zhejiang University School of Medicine
Hongqiang Cheng: Zhejiang University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26697-8

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DOI: 10.1038/s41467-021-26697-8

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