{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:21:58Z","timestamp":1791055318733,"version":"4.1.0"},"reference-count":52,"publisher":"Rockefeller University Press","issue":"13","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,12,20]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1084\/jem.20100438","type":"journal-article","created":{"date-parts":[[2010,11,23]],"date-time":"2010-11-23T03:58:19Z","timestamp":1290484699000},"page":"2855-2868","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":140,"title":["VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer"],"prefix":"10.1084","volume":"207","author":[{"given":"Maximilian J.","family":"Waldner","sequence":"first","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"},{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wirtz","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"},{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Jefremow","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Warntjen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Neufert","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Atreya","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"},{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benno","family":"Weigmann","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"},{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vieth","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Klinikum Bayreuth, D-95445 Bayreuth, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Rose-John","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Christian-Albrechts-Universit\u00e4t zu Kiel, Medical Faculty, D-23098 Kiel, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus F.","family":"Neurath","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany 1"},{"name":"Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2010,11,22]]},"reference":[{"key":"2023072617175547100_bib1","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1038\/nrc2353","article-title":"Integrins in angiogenesis and lymphangiogenesis","volume":"8","author":"Avraamides","year":"2008","journal-title":"Nat. Rev. Cancer."},{"key":"2023072617175547100_bib2","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1038\/1952","article-title":"Cancer, angiogenesis and fractals","volume":"4","author":"Baish","year":"1998","journal-title":"Nat. Med."},{"key":"2023072617175547100_bib3","first-page":"3683","article-title":"Fractals and cancer","volume":"60","author":"Baish","year":"2000","journal-title":"Cancer Res."},{"key":"2023072617175547100_bib4","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.ccr.2005.02.013","article-title":"Smoldering and polarized inflammation in the initiation and promotion of malignant disease","volume":"7","author":"Balkwill","year":"2005","journal-title":"Cancer Cell."},{"key":"2023072617175547100_bib5","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1172\/JCI200317464","article-title":"Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells","volume":"112","author":"Becker","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2023072617175547100_bib6","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.immuni.2004.07.020","article-title":"TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling","volume":"21","author":"Becker","year":"2004","journal-title":"Immunity."},{"key":"2023072617175547100_bib7","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1136\/gut.2004.061283","article-title":"In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy","volume":"54","author":"Becker","year":"2005","journal-title":"Gut."},{"key":"2023072617175547100_bib8","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1002\/1097-0142(20010215)91:4&lt;854::AID-CNCR1073&gt;3.0.CO;2-Z","article-title":"Cancer risk in patients with inflammatory bowel disease: a population-based study","volume":"91","author":"Bernstein","year":"2001","journal-title":"Cancer."},{"key":"2023072617175547100_bib9","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ccr.2009.01.002","article-title":"gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis","volume":"15","author":"Bollrath","year":"2009","journal-title":"Cancer Cell."},{"key":"2023072617175547100_bib10","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1053\/j.gastro.2008.10.028","article-title":"Transgenic expression of VEGF in intestinal epithelium drives mesenchymal cell interactions and epithelial neoplasia","volume":"136","author":"Boquoi","year":"2009","journal-title":"Gastroenterology."},{"key":"2023072617175547100_bib11","doi-asserted-by":"publisher","first-page":"re1","DOI":"10.1126\/scisignal.259re1","article-title":"Positive and negative modulation of angiogenesis by VEGFR1 ligands","volume":"2","author":"Cao","year":"2009","journal-title":"Sci. Signal."},{"key":"2023072617175547100_bib12","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1038\/nm0603-653","article-title":"Angiogenesis in health and disease","volume":"9","author":"Carmeliet","year":"2003","journal-title":"Nat. Med."},{"key":"2023072617175547100_bib13","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.4161\/cbt.7.12.6967","article-title":"Activated STAT3 is a mediator and biomarker of VEGF endothelial activation","volume":"7","author":"Chen","year":"2008","journal-title":"Cancer Biol. Ther."},{"key":"2023072617175547100_bib14","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.cell.2004.09.005","article-title":"At the crossroads of inflammation and cancer","volume":"118","author":"Clevers","year":"2004","journal-title":"Cell."},{"key":"2023072617175547100_bib15","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s10456-007-9074-0","article-title":"Angiogenesis and chronic inflammation: cause or consequence?","volume":"10","author":"Costa","year":"2007","journal-title":"Angiogenesis."},{"key":"2023072617175547100_bib16","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/nrc2403","article-title":"VEGF-targeted therapy: mechanisms of anti-tumour activity","volume":"8","author":"Ellis","year":"2008","journal-title":"Nat. Rev. Cancer."},{"key":"2023072617175547100_bib17","doi-asserted-by":"publisher","first-page":"4867","DOI":"10.3748\/wjg.14.4867","article-title":"Narrow-band imaging optical chromocolonoscopy: advantages and limitations","volume":"14","author":"Emura","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"2023072617175547100_bib18","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1161\/ATVBAHA.108.179663","article-title":"Vascular endothelial growth factor","volume":"29","author":"Ferrara","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2023072617175547100_bib19","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1146\/annurev.med.58.061705.145635","article-title":"Targeting VEGF-A to treat cancer and age-related macular degeneration","volume":"58","author":"Ferrara","year":"2007","journal-title":"Annu. Rev. Med."},{"key":"2023072617175547100_bib20","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/nbt0297-142","article-title":"I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion","volume":"15","author":"Fischer","year":"1997","journal-title":"Nat. Biotechnol."},{"key":"2023072617175547100_bib21","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1056\/NEJM197108122850711","article-title":"Tumor angiogenesis: therapeutic implications","volume":"285","author":"Folkman","year":"1971","journal-title":"N. Engl. J. Med."},{"key":"2023072617175547100_bib22","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1111\/j.1365-2362.2007.01866.x","article-title":"Activated VEGFR2\/KDR pathway in tumour cells and tumour associated vessels of colorectal cancer","volume":"37","author":"Giatromanolaki","year":"2007","journal-title":"Eur. J. Clin. Invest."},{"key":"2023072617175547100_bib23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.ccr.2009.01.001","article-title":"IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer","volume":"15","author":"Grivennikov","year":"2009","journal-title":"Cancer Cell."},{"key":"2023072617175547100_bib24","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s00011-003-1230-4","article-title":"Angiogenesis inhibition by the novel VEGF receptor tyrosine kinase inhibitor, PTK787\/ZK222584, causes significant anti-arthritic effects in models of rheumatoid arthritis","volume":"53","author":"Grosios","year":"2004","journal-title":"Inflamm. Res."},{"key":"2023072617175547100_bib25","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrclinonc.2009.110","article-title":"Targeting angiogenesis: progress with anti-VEGF treatment with large molecules","volume":"6","author":"Grothey","year":"2009","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2023072617175547100_bib26","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1126\/science.1104819","article-title":"Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy","volume":"307","author":"Jain","year":"2005","journal-title":"Science."},{"key":"2023072617175547100_bib27","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/ncponc0403","article-title":"Lessons from phase III clinical trials on anti-VEGF therapy for cancer","volume":"3","author":"Jain","year":"2006","journal-title":"Nat. Clin. Pract. Oncol."},{"key":"2023072617175547100_bib28","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1056\/NEJMra0706596","article-title":"Tumor angiogenesis","volume":"358","author":"Kerbel","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2023072617175547100_bib29","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1053\/j.gastro.2004.06.050","article-title":"Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo","volume":"127","author":"Kiesslich","year":"2004","journal-title":"Gastroenterology."},{"key":"2023072617175547100_bib30","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.cell.2009.12.046","article-title":"Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development","volume":"140","author":"Lichtenberger","year":"2010","journal-title":"Cell."},{"key":"2023072617175547100_bib31","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1593\/tlo.08118","article-title":"In vivo quantitative microvasculature phenotype imaging of healthy and malignant tissues using a fiber-optic confocal laser microprobe","volume":"1","author":"Lin","year":"2008","journal-title":"Transl. Oncol."},{"key":"2023072617175547100_bib32","first-page":"363","article-title":"VEGF induces phosphorylation of STAT3 through binding VEGFR2 in ovarian carcinoma cells in vitro","volume":"27","author":"Lu","year":"2006","journal-title":"Eur. J. Gynaecol. Oncol."},{"key":"2023072617175547100_bib33","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1111\/j.1749-6632.1992.tb39761.x","article-title":"Epithelial proliferation in response to gastrointestinal inflammation","volume":"664","author":"MacDonald","year":"1992","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2023072617175547100_bib34","doi-asserted-by":"crossref","first-page":"4618","DOI":"10.4049\/jimmunol.172.7.4618","article-title":"Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization","volume":"172","author":"Mor","year":"2004","journal-title":"J. Immunol."},{"key":"2023072617175547100_bib35","first-page":"2415","article-title":"The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6","volume":"118","author":"Mudter","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2023072617175547100_bib36","doi-asserted-by":"publisher","first-page":"1998","DOI":"10.1038\/nprot.2007.279","article-title":"An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression","volume":"2","author":"Neufert","year":"2007","journal-title":"Nat. Protoc."},{"key":"2023072617175547100_bib37","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1084\/jem.20011956","article-title":"The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn\u2019s disease","volume":"195","author":"Neurath","year":"2002","journal-title":"J. Exp. Med."},{"key":"2023072617175547100_bib38","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1084\/jem.20082683","article-title":"STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing","volume":"206","author":"Pickert","year":"2009","journal-title":"J. Exp. Med."},{"key":"2023072617175547100_bib39","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1002\/1097-0142(19930801)72:3+&lt;962::AID-CNCR2820721303&gt;3.0.CO;2-H","article-title":"The molecular biology of carcinogenesis","volume":"72","author":"Pitot","year":"1993","journal-title":"Cancer."},{"key":"2023072617175547100_bib40","first-page":"560","article-title":"Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis","volume":"118","author":"Popivanova","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2023072617175547100_bib41","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1053\/j.gastro.2008.09.064","article-title":"VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis","volume":"136","author":"Scaldaferri","year":"2009","journal-title":"Gastroenterology."},{"key":"2023072617175547100_bib42","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/nrc1187","article-title":"Targeting HIF-1 for cancer therapy","volume":"3","author":"Semenza","year":"2003","journal-title":"Nat. Rev. Cancer."},{"key":"2023072617175547100_bib43","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1126\/science.6823562","article-title":"Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid","volume":"219","author":"Senger","year":"1983","journal-title":"Science."},{"key":"2023072617175547100_bib44","first-page":"506","article-title":"Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps","volume":"62","author":"Seno","year":"2002","journal-title":"Cancer Res."},{"key":"2023072617175547100_bib45","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.yexcr.2005.11.012","article-title":"Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis","volume":"312","author":"Shibuya","year":"2006","journal-title":"Exp. Cell Res."},{"key":"2023072617175547100_bib46","doi-asserted-by":"publisher","first-page":"4434","DOI":"10.3748\/wjg.14.4434","article-title":"Molecular basis of the potential of mesalazine to prevent colorectal cancer","volume":"14","author":"Stolfi","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"2023072617175547100_bib47","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1146\/annurev.immunol.20.100301.064816","article-title":"The immunology of mucosal models of inflammation","volume":"20","author":"Strober","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"2023072617175547100_bib48","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1200\/JCO.2005.03.4645","article-title":"Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer","volume":"24","author":"Wedam","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"2023072617175547100_bib49","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1016\/j.bbrc.2006.02.100","article-title":"Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9","volume":"342","author":"Yao","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023072617175547100_bib50","doi-asserted-by":"crossref","first-page":"5846","DOI":"10.4049\/jimmunol.174.9.5846","article-title":"Arginine-rich anti-vascular endothelial growth factor (anti-VEGF) hexapeptide inhibits collagen-induced arthritis and VEGF-stimulated productions of TNF-alpha and IL-6 by human monocytes","volume":"174","author":"Yoo","year":"2005","journal-title":"J. Immunol."},{"key":"2023072617175547100_bib51","doi-asserted-by":"publisher","first-page":"129873","DOI":"10.1155\/2008\/129873","article-title":"Proinflammatory role of vascular endothelial growth factor in the pathogenesis of rheumatoid arthritis: prospects for therapeutic intervention","volume":"2008","author":"Yoo","year":"2008","journal-title":"Mediators Inflamm."},{"key":"2023072617175547100_bib52","doi-asserted-by":"publisher","first-page":"2662","DOI":"10.3748\/wjg.14.2662","article-title":"Colorectal cancer and dysplasia in inflammatory bowel disease","volume":"14","author":"Zisman","year":"2008","journal-title":"World J. Gastroenterol."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/207\/13\/2855\/1778476\/jem_20100438.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/207\/13\/2855\/1778476\/jem_20100438.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T20:14:53Z","timestamp":1690402493000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/207\/13\/2855\/40826\/VEGF-receptor-signaling-links-inflammation-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,11,22]]},"references-count":52,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2010,12,20]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20100438","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2010,11,22]]}}}