Tumor vegf:vegfr2 autocrine feed-forward loop triggers angiogenesis in lung cancer
Chatterjee S, Heukamp LC, Sioba M, Schoettle J, Wieczorek C, Peifer M, Frasca D, Koker M, Koenig K, Meder L, Rauh D, Buettner R, Wolf J, Brekken RA, Neumaier B, Christofori G, Thomas RK, Ulrich RT (2013)
Publication Type: Journal article
Publication year: 2013
Journal
Book Volume: 123
Pages Range: 1732-1740
Journal Issue: 4
DOI: 10.1172/JCI65385
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 with CRIS profile
Involved external institutions
Universität zu Köln
Germany (DE)
Universitätsklinikum Köln
Germany (DE)
University of Texas Southwestern Medical Center (UT Southwestern)
United States (USA) (US)
Universität Basel
Switzerland (CH)
Germany (DE)
Universitätsklinikum Köln
Germany (DE)
University of Texas Southwestern Medical Center (UT Southwestern)
United States (USA) (US)
Universität Basel
Switzerland (CH)
How to cite
APA:
Chatterjee, S., Heukamp, L.C., Sioba, M., Schoettle, J., Wieczorek, C., Peifer, M.,... Ulrich, R.T. (2013). Tumor vegf:vegfr2 autocrine feed-forward loop triggers angiogenesis in lung cancer. Journal of Clinical Investigation, 123(4), 1732-1740. https://dx.doi.org/10.1172/JCI65385
MLA:
Chatterjee, Sampurna, et al. "Tumor vegf:vegfr2 autocrine feed-forward loop triggers angiogenesis in lung cancer." Journal of Clinical Investigation 123.4 (2013): 1732-1740.
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