title: The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance.
abstract: 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.
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Lejla
authors.initials: L
authors.lastname: Alidzanovic
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Starlinger
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Dominic
authors.initials: D
authors.lastname: Schauer
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Maier
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Feldman
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Buchberger
authors.affiliation: Department of Pathology, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Stift
authors.affiliation: Department of Neuroimmunology, Medical University of Vienna, Center for Brain Research, 1090 Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Koeck
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Lorand
authors.initials: L
authors.lastname: Pop
authors.affiliation: Department of Internal Medicine, Hospital of The Merciful Brothers, 1020 Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Gruenberger
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.|Current address: Department of Surgery I, Rudolf Foundation Clinic, 1030 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruenberger
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Brostjan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use*; D001792:Blood Platelets / Q000166:cytology; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
keywords: bevacizumab; colorectal carcinoma; liver metastasis; plasma; vascular endothelial growth factor