Research Papers:

The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance

Lejla Alidzanovic, Patrick Starlinger, Dominic Schauer, Thomas Maier, Alexandra Feldman, Elisabeth Buchberger, Judith Stift, Ulrike Koeck, Lorand Pop, Birgit Gruenberger, Thomas Gruenberger _ and Christine Brostjan

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Oncotarget. 2016; 7:57197-57212. https://doi.org/10.18632/oncotarget.11084

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Lejla Alidzanovic1, Patrick Starlinger1, Dominic Schauer1, Thomas Maier1, Alexandra Feldman1, Elisabeth Buchberger1, Judith Stift2, Ulrike Koeck3, Lorand Pop1, Birgit Gruenberger4, Thomas Gruenberger1,5, Christine Brostjan1

1Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria

2Department of Pathology, Medical University of Vienna, General Hospital, 1090 Vienna, Austria

3Department of Neuroimmunology, Medical University of Vienna, Center for Brain Research, 1090 Vienna, Austria

4Department of Internal Medicine, Hospital of The Merciful Brothers, 1020 Vienna, Austria

5Current address: Department of Surgery I, Rudolf Foundation Clinic, 1030 Vienna, Austria

Correspondence to:

Thomas Gruenberger, email: thomas.gruenberger@wienkav.at

Christine Brostjan, email: christine.brostjan@meduniwien.ac.at

Keywords: bevacizumab, colorectal carcinoma, liver metastasis, plasma, vascular endothelial growth factor

Received: January 28, 2016     Accepted: July 26, 2016     Published: August 5, 2016


Vascular endothelial growth factor (VEGF) has become a major target in cancer treatment as it promotes tumor angiogenesis. Therapy with anti-VEGF antibody bevacizumab reportedly induces high levels of circulating VEGF which may potentially contribute to resistance. Based on animal or computational models, mechanisms of VEGF induction by bevacizumab have been proposed but not verified in the clinical setting. Hence, we evaluated sixty patients with colorectal cancer metastases for changes in plasma VEGF during neoadjuvant/conversion and adjuvant chemotherapy with or without bevacizumab. VEGF expression was assessed in tissue sections of liver metastases. The VEGF source was investigated with in vitro cultures of tumor, endothelial cells, fibroblasts and platelets, and potential protein stabilization due to anti-VEGF therapy was addressed. A VEGF rise was observed in blood of bevacizumab patients but not in chemotherapy controls, and VEGF was found to be largely complexed by the antibody. A comparable VEGF increase occurred in the presence (neoadjuvant) and absence of the tumor (adjuvant). Accordingly, VEGF expression in tumor tissue was not determined by bevacizumab treatment. Investigations with isolated cell types did not reveal VEGF production in response to bevacizumab. However, antibody addition to endothelial cultures led to a dose-dependent blockade of VEGF internalization and hence stabilized VEGF in the supernatant. In conclusion, the VEGF rise in cancer patients treated with bevacizumab is not originating from the tumor. The accumulation of primarily host-derived VEGF in circulation can be explained by antibody interference with receptor-mediated endocytosis and protein degradation. Thus, the VEGF increase in response to bevacizumab therapy should not be regarded as a tumor escape mechanism.

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