VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer

• Published in: The Journal of experimental medicine 2010-12, Vol.207 (13), p.2855-2868
• Main Authors: Waldner, Maximilian J, Wirtz, Stefan, Jefremow, André, Warntjen, Moritz, Neufert, Clemens, Atreya, Raja, Becker, Christoph, Weigmann, Benno, Vieth, Michael, Rose-John, Stefan, Neurath, Markus F
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Proliferation - drug effects; Cells, Cultured; Colitis - chemically induced; Colitis - complications; Colonic Neoplasms - etiology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Dextran Sulfate; Endothelial Cells - metabolism; Epithelial Cells - metabolism; Gene Expression; Humans; Immunohistochemistry; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Up-Regulation; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20100438

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.