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

• DOI: 10.1172/jci65385
• Publication Date: 2013-03-02T07:11:47Z
• 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
• Keywords: Primary tumor; Tumor progression

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