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Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer
Sampurna Chatterjee,1 Lukas C. Heukamp,2 Maike Siobal,1 Jakob Schöttle,1 Caroline Wieczorek,1 Martin Peifer,1 Davide Frasca,2 Mirjam Koker,1 Katharina König,2 Lydia Meder,2 Daniel Rauh,3 Reinhard Buettner,2 Jürgen Wolf,4 Rolf A. Brekken,5 Bernd Neumaier,1 Gerhard Christofori,6 Roman K. Thomas,2,7 and Roland T. Ullrich1,4
1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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1Max 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. 2Institute of Pathology, University Hospital Medical School, Cologne, Germany. 3Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany. 4Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. 5Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6Institute of Biochemistry and Genetics, Department of Biomedicine, Basel, Switzerland. 7Department of Translational Genomics, University of Cologne, Cologne, Germany.
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Published July 1, 2013 - More info
J Clin Invest. 2013;123(7):3183–3183. https://doi.org/10.1172/JCI70810.
© 2013 The American Society for Clinical Investigation
Related article:
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
Original citation: J. Clin. Invest. 2013;123(4):1732–1740. doi:10.1172/JCI65385.
Citation for this corrigendum: J. Clin. Invest. 2013;123(7):3183. doi:10.1172/JCI70810.
The affiliations for Roman K. Thomas were incorrect. The correct affiliations list is above.
The authors regret the error.
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ISSN: 0021-9738 (print), 1558-8238 (online)