Malignant Mesothelioma: Mechanism of Carcinogenesis

Abstract

Almost 60 years ago, malignant mesothelioma (MM) was acknowledged as a specific cancer related to the inhalation of asbestos fibers (Wagner et al., Br J Ind Med. 17:260–271, 1960). Its strong association with asbestos exposure triggered the development of researches. They consisted of epidemiological studies to know the risk factors that explain MM occurrence in the population and of experimental studies to understand MM biological development as a neoplastic disease. Since then, MM remains a rare and highly aggressive cancer that prompts researches to better manage patients with MM and to offer efficient therapies. To achieve this goal, a solid knowledge of the mechanisms of mesothelial carcinogenesis is needed and deserves basic researches to progress. So far, our knowledge is based on pathophysiological and toxicological researches and from biological and molecular studies using MM tissue tumor samples and cell lines from humans and experimental animals. Most experimental studies have been based on the cellular and/or animal responses to asbestos fibers and in genetically modified mice, demonstrating the genotoxic effect of asbestos and relationship with MM induction. The development of large-scale analyses allowing global integration of the molecular networks involved in mesothelial cell transformation should increase our understanding of mesothelial carcinogenesis. In human, MM tumors appeared as heterogeneous entities, based on morphological patterns and molecular specificities including gene mutations. The recent development of high-throughput methods allowed classification of MM according to their histological type, genomic and epigenomic characteristics, and deregulated pathways. The aim of the present review is to propose a potential mechanism of mesothelial carcinogenesis by integrating data, underlying the mechanisms that may be shared with other types of fibers that may pose current health issue.KeywordsMalignant mesotheliomaMesothelial carcinogenesisAsbestosPleural carcinogenesisGenomic changesEpigenetic changesSignaling pathways