title: VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis.
abstract: OBJECTIVE
  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.
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Sebastian
authors: S
authors: Foersch
authors: Fritz Lipmann Institute, Leibniz Institute for Age Research, Jena, Germany.
authors: Tobias
authors: T
authors: Sperka
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Christina
authors: C
authors: Lindner
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Astrid
authors: A
authors: Taut
authors: Fritz Lipmann Institute, Leibniz Institute for Age Research, Jena, Germany.
authors: Karl L
authors: KL
authors: Rudolph
authors: Department of Pathology, Dresden University of Technology, Dresden, Germany.
authors: Georg
authors: G
authors: Breier
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Frank
authors: F
authors: Boxberger
authors: Department of Pathology, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Tilman T
authors: TT
authors: Rau
authors: Department of Pathology, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Arndt
authors: A
authors: Hartmann
authors: Division of Molecular and Experimental Surgery, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Michael
authors: M
authors: Stürzl
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Nadine
authors: N
authors: Wittkopf
authors: Division of Molecular and Experimental Surgery, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Lisa
authors: L
authors: Haep
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Stefan
authors: S
authors: Wirtz
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
authors: Markus F
authors: MF
authors: Neurath
authors: Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany. Electronic address: maximilian.waldner@uk-erlangen.de.
authors: Maximilian J
authors: MJ
authors: Waldner
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D003092:Colitis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D016264:Dextran Sulfate; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt
keywords: Angiogenesis; Colon Cancer; Inflammation; Mouse Model