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

Gastroenterology. 2015 Jul;149(1):177-189.e10. doi: 10.1053/j.gastro.2015.03.016. Epub 2015 Mar 19.

Abstract

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.

Keywords: Angiogenesis; Colon Cancer; Inflammation; Mouse Model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Bevacizumab
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics*
  • Colitis / complications
  • Colitis / genetics*
  • Colitis / pathology
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Disease-Free Survival
  • Female
  • HCT116 Cells
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-akt / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / genetics*

Substances

  • Antibodies, Monoclonal, Humanized
  • Bevacizumab
  • Dextran Sulfate
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-akt