How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing and somatic mutations

Abstract

Chronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development. Macrophages, mesothelial precursor cells, cytokines and growth factors accumulated in the peritoneal lavage. Transcriptome profiling revealed YAP/TAZ activation in inflamed mesothelium with further activation in tumors, paralleled by increased levels of cells with nuclear YAP/TAZ. Arg1 was one of the highest upregulated genes in inflamed tissue and tumor. Inflamed tissue showed increased levels of single nucleotide variations, with an RNA-editing signature, which were even higher in the tumor samples. Subcutaneous injection of asbestos-treated, but tumor-free mice with syngeneic mesothelioma tumor cells resulted in a significantly higher incidence of tumor growth when compared to naive mice supporting the role of the environment in tumor progression.\n\nHighlightsO_LIAsbestos increases levels of cytokines and growth factors in mesothelium environment\nC_LIO_LIRecruitment of macrophages and mesothelial precursor cells prior to tumor development\nC_LIO_LIYAP/TAZ signaling upregulated in pre-neoplastic tissues and cancer\nC_LIO_LIIncreased RNA-editing and somatic mutations as early steps in tumor development\nC_LI