title: 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.
authors.affiliation: Department of Neurosurgery, Grosshadern Hospital, Ludwig-Maximilian University, Munich, Germany. stefan.grau@uk-koeln.de
authors.forename: S
authors.initials: S
authors.lastname: Grau
authors.forename: J
authors.initials: J
authors.lastname: Thorsteinsdottir
authors.forename: L
authors.initials: L
authors.lastname: von Baumgarten
authors.forename: F
authors.initials: F
authors.lastname: Winkler
authors.forename: J-C
authors.initials: JC
authors.lastname: Tonn
authors.forename: C
authors.initials: C
authors.lastname: Schichor
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry / Q000379:methods; D005910:Glioma / Q000473:pathology*; D006801:Humans; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D042582:Vascular Endothelial Growth Factor C / Q000276:immunology / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000276:immunology / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D061067:Antibodies, Monoclonal, Humanized; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013778:Tetrazolium Salts; D013844:Thiazoles; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D000068258:Bevacizumab; C022616:thiazolyl blue