Effects of Bevacizumab on Autocrine VEGF Stimulation in Bladder Cancer Cell LinesVideira P.A.a · Piteira A.R.a · Cabral M.G.a · Martins C.a · Correia M.a · Severino P.a · Gouveia H.a · Carrascal M.a · Almeida J.F.a · Trindade H.a · Santos L.L.b
aCEDOC, Departamento de Imunologia, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Lisboa, and bDepartamento de Oncologia Cirúrgica, Instituto Português de Oncologia do Porto e Universidade Fernando Pessoa, Porto, Portugal
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Introduction: A functional vascular endothelial growth factor A (VEGF-A) autocrine loop is crucial for bladder cancer cell survival. We reasoned that treatment with the anti-VEGF antibody bevacizumab may result either in cell growth prevention or in the cell adaptation to compensate VEGF deprivation. Methods: The cytotoxicity of different levels of bevacizumab and its effect on the gene expression was analyzed in human bladder cancer cell lines. Results: Inhibition of bladder cancer cell proliferation was observed at >2.5 mg/ml of bevacizumab. Non-muscle-invasive bladder cancer cells expressed high concentrations of VEGF-A, and were less susceptible to bevacizumab inhibition. At 0.5 mg/ml (FDA approved concentration) of bevacizumab, cells increase their expression of VEGF-A, VEGF-A receptors and related growth factors. Conclusions: Bevacizumab cytotoxicity is only observed at high concentration, and it is inversely correlated with the basal VEGF-A expression of the bladder cancer cells. This is the first report showing that, at clinical bevacizumab concentrations, cancer cells compensate the VEGF-A blockade, by improving the expression of VEGF-A and related genes, highlighting the need to follow the patient’s adaptation response to bevacizumab treatment.
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