title: VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer.
abstract: Whereas the inhibition of vascular endothelial growth factor (VEGF) has shown promising results in sporadic colon cancer, the role of VEGF signaling in colitis-associated cancer (CAC) has not been addressed. We found that, unlike sporadic colorectal cancer and control patients, patients with CAC show activated VEGFR2 on intestinal epithelial cells (IECs). We then explored the function of VEGFR2 in a murine model of colitis-associated colon cancer characterized by increased VEGFR2 expression. Epithelial cells in tumor tissue expressed VEGFR2 and responded to VEGF stimulation with augmented VEGFR2-mediated proliferation. Blockade of VEGF function via soluble decoy receptors suppressed tumor development, inhibited tumor angiogenesis, and blocked tumor cell proliferation. Functional studies revealed that chronic inflammation leads to an up-regulation of VEGFR2 on IECs. Studies in conditional STAT3 mutant mice showed that VEGFR signaling requires STAT3 to promote epithelial cell proliferation and tumor growth in vivo. Thus, VEGFR-signaling acts as a direct growth factor for tumor cells in CAC, providing a molecular link between inflammation and the development of colon cancer.
authors.affiliation: Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany.
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Waldner
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: André
authors.initials: A
authors.lastname: Jefremow
authors.forename: Moritz
authors.initials: M
authors.lastname: Warntjen
authors.forename: Clemens
authors.initials: C
authors.lastname: Neufert
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Benno
authors.initials: B
authors.lastname: Weigmann
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000150:complications; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate; D042783:Endothelial Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D016264:Dextran Sulfate; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2