Bevacizumab can induce reactivity to VEGF-C and -D in human brain and tumour derived endothelial cells

Abstract

Though clinical trials demonstrated effectiveness of the anti-VEGF antibody bevacizumab (Avastin) in adjuvant therapies for some solid tumours, there are rather few experimental data about cellular effects of bevacizumab on tumour cells and tumour associated endothelial cells. Recent reports demonstrate resistance mechanisms and secondary re-angiogenesis after a transient normalization of tumour vessels. Therefore we investigated the influence of bevacizumab on human glioma cells and human brain derived as well as tumour derived endothelial cells focussing on the role of VEGF-C and -D as potential alternative pro-angiogenic factors. Bevacizumab treatment showed no influence on proliferation after short term exposure (1-5 days) but slowed down endothelial cell proliferation by 25-30% after 14 days treatment. There was no significant induction of apoptosis after short or long term exposure. Tube formation capabilities were significantly impaired by bevacizumab with a continuing effect after 14 days of treatment even after omitting the antibody. VEGF-C and -D had no effect on endothelial cells in untreated or short term treatment groups. However, cells developed responsiveness to these factors in terms of increased proliferation and tube formation after 14 days bevacizumab treatment. Furthermore, bevacizumab induced expression of VEGF-C and -D in glioma cells. Treatment with bevacizumab may induce alterations in human brain and tumour endothelial cells leading to escape mechanisms from anti-VEGF therapy. VEGF-C and -D thus might act as alternative pro-angiogenic factors during anti-VEGF therapy.

Roundabout4 Suppresses Glioma-Induced Endothelial Cell Proliferation, Migration and Tube Formation in Vitro by Inhibiting VEGR2-Mediated PI3K/AKT and FAK Signaling Pathways

“…6E, F). VEGF signaling pathway, known as a molecular switch of tumor angiogenesis [40], plays a critical role in various stages of angiogenesis including endothelial cell proliferation [41], migration [8] and tube formation [42]. The angiogenic response of VEGF is mainly mediated by the activation of VEGFR2 [43].…”

The Propeptides of VEGF-D Determine Heparin Binding, Receptor Heterodimerization, and Effects on Tumor Biology

“…Clinicopathological as well as experimental data indicate that the VEGF-D signaling pathway may be a therapeutic target for restricting the spread of cancer (23,24). Further, it has been proposed that VEGF-D is an alternative mediator of tumor angiogenesis to VEGF-A (25,26), that might contribute to mechanisms of resistance to bevacizumab, a widely used anti-cancer drug targeting VEGF-A (27). The analysis of VEGF-D in clinical samples, such as tumor tissues, is complicated by the fact that this is a proteolytically processed protein (28), which can be detected in various forms of different sizes and subunit compositions.…”

Photodynamic Therapy in Combination with Antiangiogenic Approaches Improve Tumor Inhibition

“…Avastin and Erbitux were used successfully to reduce and inhibit tube formation, thus signifying their role in blocking major angiogenic processes. Similarly, another study demonstrated that bevacizumab could significantly impair tube formation capabilities in tumor derived endothelial cells and also noted a continuing effect after 14 days of treatment even after omitting the antibody (Grau et al, 2011). Treatment with Cetuximab has also shown to reduce cell-to-cell interaction of human umbilical vascular endothelial cells (HUVEC), resulting in disruption of tube formation (S. M. Huang et al, 2002).…”