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.

A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

“…The post-treatment VEGF changes in our study are based on small number of patients, but are consistent with anti-angiogenic properties of IL-12 [3]. Although the mechanisms underlying increased VEGF levels following anti-angiogenic therapy are unclear, several mechanisms have been proposed and include the following: increased VEGF production by tumor, relocalization from tissue to circulation, or host-blockade of VEGF clearance [17–19]. …”

“…3C) but decreased by ~50% in PR group. A modest increase in plasma VEGF post GEN-1 therapy is similar in magnitude of the increase seen with the use of anti-VEGF antibodies or tyrosine kinase inhibitors in cancer patients [16,17]. The post-treatment VEGF changes in our study are based on small number of patients, but are consistent with anti-angiogenic properties of IL-12 [3].…”

MicroRNA-26b inhibits the tumor growth of human liver cancer through the PI3K/Akt and NF-κB/MMP-9/VEGF pathways

“…In addition, we demonstrated that the growth, infiltration and metastasis of malignant tumors require angiogenesis. As an important multi-functional angiogenesis factor, VEGF exerts its function by specifically acting on receptors on the vascular endothelial cell surface, which cannot only promote mitosis and proliferation of vascular endothelial cells but also enhance capillary permeability (23). upregulated VEGF expression can be observed in all malignant tumors, and thus it plays a vital role in angiogenesis, infiltration and metastasis of tumors (24).…”

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…It is the first anti-angiogenic drug approved for clinical application, and it has proved increased efficiency in multiple malignancy types, including colorectal cancer or glioblastoma [99,[105][106][107][108]. The intravenous administration of bevacizumab results in increased VEGF blood levels, which is mostly antibody-bound and inactive [106]. However, treatment with bevacizumab has been associated with several side effects, including hypertension, proteinuria, and gastrointestinal perforations and bleeding.…”