1. VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis
- Author
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Stefan Wirtz, Tilman T. Rau, Maximilian J. Waldner, Karl Lenhard Rudolph, Georg Breier, Tobias Sperka, Michael Stürzl, Arndt Hartmann, Nadine Wittkopf, Astrid Taut, Markus F. Neurath, Frank Boxberger, Lisa Haep, Sebastian Foersch, and Christina Lindner
- Subjects
Senescence ,Male ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Colorectal cancer ,Mice, Transgenic ,Biology ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Antibodies, Monoclonal, Humanized ,Disease-Free Survival ,chemistry.chemical_compound ,Mice ,medicine ,Animals ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cellular Senescence ,Cell Proliferation ,Hepatology ,Dextran Sulfate ,Gastroenterology ,Cancer ,respiratory system ,medicine.disease ,Colitis ,HCT116 Cells ,Vascular Endothelial Growth Factor Receptor-2 ,Vascular endothelial growth factor ,Bevacizumab ,Disease Models, Animal ,chemistry ,cardiovascular system ,Cancer research ,Female ,Carcinogenesis ,Colorectal Neoplasms ,Proto-Oncogene Proteins c-akt - 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.
- Published
- 2014