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.
Highlights
Angiogenesis is the process of capillary sprouting from pre-existing vessels and is essential to many physiological and pathological conditions [1]
A Vascular endothelial growth factor (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
Among the patients who were enrolled in our study and received neoadjuvant treatment with chemotherapy, forty-five were treated with bevacizumab and fifteen without
Summary
Angiogenesis is the process of capillary sprouting from pre-existing vessels and is essential to many physiological and pathological conditions [1]. The role of angiogenesis in supporting tumor growth and metastasis has been a major focus of cancer research over the past decades and vascular endothelial growth factor (VEGF). VEGF-A (generally called VEGF) is of particular importance in tumor angiogenesis. It is secreted by cancer cells [4] and various other cell types, including stromal fibroblasts [5], endothelial cells [6] and platelets [7]. VEGF-A binds to VEGFR-1 and VEGFR-2, which are predominantly expressed by endothelial cells while VEGFR-3 is mostly found on lymphatic vessels and interacts with VEGF-C and VEGF-D. By binding to its receptors, VEGF induces endothelial cell mitosis, migration, survival, and vascular permeability [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
