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Chatterjee, Sampurna and Heukamp, Lukas (2013). Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. JCI. pp. 1732-1740.

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Abstract

The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chatterjee, Sampurna sampurna.steele@gmail.com UNSPECIFIED UNSPECIFIED Heukamp, Lukas heukamp@newoncology.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-65917
Journal or Publication Title:	JCI
Page Range:	pp. 1732-1740
Date:	2013
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Zentrum für Molekulare Medizin
Subjects:	Natural sciences and mathematics Life sciences
Related URLs:	http://www.jci.org/articles/view/65385
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/6591