VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis

Gastroenterology
Sebastian FoerschMaximilian J Waldner

Abstract

Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC). CAC was induced in VEGFR2(ΔIEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate. Tumor development and inflammation were determined by endoscopy. Colorectal tissues were collected for immunoblot, immunohistochemical, and quantitative polymerase chain reaction analyses. Findings from mouse tissues were confirmed in human HCT116 colorectal cancer cells. We analyzed colorectal tumor samples from patients before and after treatment with bevacizumab. After colitis induction, VEGFR2(ΔIEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(ΔIEC) mice were in senescence than tumor cells from control mice. We found VEGFR2 to activate phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, resulting in inactivation of p21 in HCT116 cells. Inhibitors of VEGFR2 and AKT induced senescence in HCT116 cells. Tumor cell s...Continue Reading

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Citations

Nov 13, 2015·Critical Reviews in Oncology/hematology·Jonathan P EvansNeil R Kitteringham
Apr 8, 2017·Cell Death and Differentiation·Wenjing XingHuan Ren
Sep 25, 2017·Der Pathologe·S Foersch
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Jan 21, 2021·Biomedicines·Kyusang HwangSukmook Lee
Jun 8, 2021·Cancer Biomarkers : Section a of Disease Markers·Ganbiao WangYongxiang Li

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