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

Chatterjee, Sampurna and Heukamp, Lukas (2013) Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. JCI. pp. 1732-1740.

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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.

    Item Type: Article
    Creators:
    CreatorsEmail
    Chatterjee, Sampurnasampurna.steele@gmail.com
    Heukamp, Lukasheukamp@newoncology.de
    URN: urn:nbn:de:hbz:38-65917
    Journal or Publication Title: JCI
    Subjects: Natural sciences and mathematics
    Life sciences
    Faculty: Mathematisch-Naturwissenschaftliche Fakultät
    Divisions: Mathematisch-Naturwissenschaftliche Fakultät > ZMMK
    Language: English
    Date: 2013
    Date Type: Completion
    Full Text Status: Public
    Related URLs:
    Date Deposited: 05 Apr 2016 13:56:04
    URI: http://kups.ub.uni-koeln.de/id/eprint/6591

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