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

Foersch, Sebastian; Sperka, Tobias; Lindner, Christina; Taut, Astrid; Rudolph, Karl L; Breier, Georg; Boxberger, Frank; Rau, Tilman; Hartmann, Arndt; Stürzl, Michael; Wittkopf, Nadine; Haep, Lisa; Wirtz, Stefan; Neurath, Markus F; Waldner, Maximilian J (2015). VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis. Gastroenterology, 149(1), 177-189.e10. Elsevier 10.1053/j.gastro.2015.03.016

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BACKGROUND & AIMS 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). METHODS 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. RESULTS 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 senescence promoted an anti-tumor immune response by CD8(+) T cells in mice. Patients whose tumor samples showed an increase in the proportion of senescent cells after treatment with bevacizumab had longer progression-free survival than patients in which the proportion of senescent tumor cells did not change before and after treatment. CONCLUSIONS Inhibition of VEGFR2 signaling leads to senescence of human and mouse colorectal cancer cells. VEGFR2 interacts with phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT to inactivate p21. Colorectal tumor senescence and p21 level correlate with patient survival during treatment with bevacizumab.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology

UniBE Contributor:

Rau, Tilman

ISSN:

0016-5085

Publisher:

Elsevier

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

13 Jul 2015 16:17

Last Modified:

05 Nov 2015 13:46

Publisher DOI:

10.1053/j.gastro.2015.03.016

PubMed ID:

25797700

Uncontrolled Keywords:

Angiogenesis; Colon Cancer; Inflammation; Mouse Model

BORIS DOI:

10.7892/boris.70193

URI:

https://boris.unibe.ch/id/eprint/70193

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