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Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer
Sampurna Chatterjee, … , Roman K. Thomas, Roland T. Ullrich
Sampurna Chatterjee, … , Roman K. Thomas, Roland T. Ullrich
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1732-1740. https://doi.org/10.1172/JCI65385.
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Research Article Oncology Article has an altmetric score of 14

Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer

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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.

Authors

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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Figure 1

A VEGF:VEGFR2 feed-forward loop in tumor cells boosts VEGF secretion.

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A VEGF:VEGFR2 feed-forward loop in tumor cells boosts VEGF secretion.
(A...
(A) VEGFR2 expression data from the 53 NSCLC cell lines were obtained using Affymetrix U133A arrays (21). (B) Mice with established tumors (H1975) were treated with ZD6474, and PET imaging was performed on day 0 (before start of therapy) and at the indicated time points after treatment (left panels, [18F]FLT-PET; right panels, [11C]MET-PET). (C) Substitution of Val916 by Met at the gatekeeper position of VEGFR2 creates a steric clash with the inhibitor and prevents ZD6474 from binding. (D) Secretion of VEGF by H1975, H441, and (E) H1975 mutant cells (VEGFR2V916M) was determined in vitro by ELISA (D) following stimulation with increasing amounts of recombinant VEGF. H1975 and H441 cells were stimulated with the indicated concentrations of VEGF (V) and pretreated with the indicated compounds (ZD6474 [Z], 1 μM; rapamycin [R], 100 nM). (F and G) Cells were treated with VEGF and the indicated dose of ZD6474, and phosphorylation of VEGFR2 was determined by immunoprecipitation. (F) The impact on activation of downstream signaling was determined by immunoblotting. (H) H1975 mutant cells (VEGFR2V916M) or the wild-type control cells were injected into nude mice and treated with ZD6474 or vehicle on day 1 after tumor cell injections.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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