Bevacizumab induces inflammation in MDA-MB-231 breast cancer cell line and in a mouse model

• Published in: Cellular signalling 2019-01, Vol.53, p.400-412
• Main Authors: EL-Hajjar, Layal, Jalaleddine, Nour, Shaito, Abdullah, Zibara, Kazem, Kazan, Jalal M., El-Saghir, Jamal, El-Sabban, Marwan
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - pharmacology; Bevacizumab - adverse effects; Bevacizumab - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Cell Line, Tumor; Connexin 43; Disease Models, Animal; Female; Humans; Inflammation; Inflammation - chemically induced; Metastasis; Mice; Neovascularization, Pathologic - drug therapy; NF-κB; Tumor Microenvironment - drug effects
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2018.11.007

Bevacizumab or Avastin® (Av) is an anti-vascular endothelial growth factor agent. It does not improve survival of breast cancer patients due to development of refractoriness. Av treatment was shown to increase inflammation in a diabetic mouse model, and also to induce epithelial-to-mesenchymal transition of non-transformed breast epithelia. This study aimed to understand if the Av-induced inflammatory microenvironment could be a mechanism of Av refractoriness. Expression profiles of inflammatory mediators, in vitro in MDA-MB-231 cells, in vivo in a mouse model xenografted with MDA-MB-231 cells and from archived cases of human breast carcinoma tissues were evaluated. Gap junctions are also crucial for angiogenesis and tumor cell extravasation. The effect of connexin 43 (Cx43) overexpression on the expression of inflammatory markers in MDA-MB-231 cells treated with Av was assessed. MDA-MB-231 cells, control or overexpressing Cx43, were used in this study. Proliferation and invasion assays were performed. Quantitative PCR, ELISA and western blotting were performed to assess the regulation of inflammatory mediators and other factors upon Av treatment. Immunofluorescence was performed to document the translocation of Nuclear Factor-kappa B p65. Breast cancer tissues had elevated transcriptional levels of inflammatory mediators. Av treatment increased expression levels of inflammatory mediators and metastatic factors in vitro and in vivo. Interestingly, overexpressing Cx43 in MDA-MB-231 cells alleviated the inflammatory effects induced by Av treatment. This study attributes Av refractoriness to the Av therapy-induced inflammatory microenvironment. •VEGF stimulates angiogenesis especially during cancer progression.•Cancer patients usually become refractive to treatment with avastin (Av), which targets VEGF.•Cx43 is a gap junction protein downregulated in several cancers and whose upregulation inhibits tumor growth.•Av increases inflammation in the tumor microenvironment.•Upregulation of Cx43 reversed the inflammatory state induced by Av.•Av anti-angiogenesis therapy should be more effective in Cx43 expressing tumors.