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

Försch S, Sperka T, Lindner C, Taut A, Rudolph KL, Breier G, Boxberger F, Rau T, Hartmann A, Stürzl M, Wittkopf N, Haep L, Wirtz S, Neurath M, Waldner M (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Gastroenterology Elsevier

Publisher: WB Saunders

Book Volume: 149

Pages Range: 177-189.e10

Journal Issue: 1

DOI: 10.1053/j.gastro.2015.03.016

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(?IEC) 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(?IEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(?IEC) 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.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.

Authors with CRIS profile

Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Lisa Haep Professur für Molekulare und Experimentelle Chirurgie Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I Maximilian Waldner Professur für Funktionelle Bildgebung in der Medizin

Involved external institutions

Technische Universität Dresden DE Germany (DE) Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut (FLI) DE Germany (DE)

How to cite

APA:

Försch, S., Sperka, T., Lindner, C., Taut, A., Rudolph, K.L., Breier, G.,... Waldner, M. (2015). VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis. Gastroenterology, 149(1), 177-189.e10. https://doi.org/10.1053/j.gastro.2015.03.016

MLA:

Försch, Sebastian, et al. "VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis." Gastroenterology 149.1 (2015): 177-189.e10.

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