Document Detail

Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer.
MedLine Citation:
PMID:  23454747     Owner:  NLM     Status:  MEDLINE    
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.
Sampurna Chatterjee; Lukas C Heukamp; Maike Siobal; Jakob Schöttle; Caroline Wieczorek; Martin Peifer; Davide Frasca; Mirjam Koker; Katharina König; Lydia Meder; Daniel Rauh; Reinhard Buettner; Jürgen Wolf; Rolf A Brekken; Bernd Neumaier; Gerhard Christofori; Roman K Thomas; Roland T Ullrich
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-09     Completed Date:  2013-05-20     Revised Date:  2013-09-12    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1732-40     Citation Subset:  AIM; IM    
Max Planck Institute for Neurological Research, with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, Cologne, Germany.
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MeSH Terms
Antineoplastic Agents / pharmacology
Carcinoma, Non-Small-Cell Lung / blood supply*,  metabolism,  pathology
Cell Line, Tumor
Cell Transformation, Neoplastic / metabolism
Feedback, Physiological / drug effects*
Lung Neoplasms / blood supply*,  metabolism,  pathology
MAP Kinase Signaling System
Mice, Nude
Neovascularization, Pathologic / metabolism*
Vascular Endothelial Growth Factor A / metabolism*,  secretion
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors,  metabolism*
Reg. No./Substance:
0/Antineoplastic Agents; 0/N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine; 0/PD 0325901; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; EC Endothelial Growth Factor Receptor-2
Erratum In:
J Clin Invest. 2013 Jul 1;123(7):3183

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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