Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma

Front Toxicol. 2023 Jun 27:5:1200650. doi: 10.3389/ftox.2023.1200650. eCollection 2023.


Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit.

Keywords: GM mouse model; asbestos; cancer therapy; macrophages; mesothelioma.

Grants and funding

Funding was provided by the Mick Knighton Mesothelioma Research Fund and British Lung Foundation project grant MKMRFPG18-4; the June Hancock Mesothelioma Research Foundation pilot grant Meso-ORIGINS; British Lung Foundation studentship APHD13-5; CRUK Early detection programme IAMMED-Meso EDDPGM-Nov21\100001; CRUK Accelerator award PREDICT-Meso A29372; CRUK Beatson Institute core facilities grants A17196, A23983 & A25006; MM was supported by Medical Research Council Intramural Grant in Aid funding MC_UU_00025/4 RG94521. CR was supported by a Scottish Govt. Chief Scientist Office clinical lectureship, PCL/18/06.