title: Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer.
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: 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.
authors: Sampurna
authors: S
authors: Chatterjee
authors: Lukas C
authors: LC
authors: Heukamp
authors: Maike
authors: M
authors: Siobal
authors: Jakob
authors: J
authors: Schöttle
authors: Caroline
authors: C
authors: Wieczorek
authors: Martin
authors: M
authors: Peifer
authors: Davide
authors: D
authors: Frasca
authors: Mirjam
authors: M
authors: Koker
authors: Katharina
authors: K
authors: König
authors: Lydia
authors: L
authors: Meder
authors: Daniel
authors: D
authors: Rauh
authors: Reinhard
authors: R
authors: Buettner
authors: Jürgen
authors: J
authors: Wolf
authors: Rolf A
authors: RA
authors: Brekken
authors: Bernd
authors: B
authors: Neumaier
authors: Gerhard
authors: G
authors: Christofori
authors: Roman K
authors: RK
authors: Thomas
authors: Roland T
authors: RT
authors: Ullrich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives; D025461:Feedback, Physiological / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010880:Piperidines; D011799:Quinazolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C506614:mirdametinib; D004159:Diphenylamine; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib