Figure 3.

A schematic diagram indicating the main players in transformation of mesothelial cells to MMs. Several receptors are activated directly by asbestos or oxidants, leading to phosphorylation of RTKs, mitogen-activated protein kinases, and stimulation of growth-promoting or antiapoptotic (survival) pathways that also may be initiated by cytokines such as TNF-α produced by macrophages or mesothelial cells.^40,49 Cell-signaling cascades, such as ERKs, may govern plasticity of mesothelial cells and may impinge on early-response proto-oncogenes, such as fra-1, to modulate c-Jun recruitment to form AP-1, NF-κB, FOXO, and other transcription factors; these encode genes promoting cell proliferation, inflammation, and genetic instability. In subsets of MMs or mesothelial cells exposed to pathogenic asbestos fibers, genetic changes over time may include transient mutations by ROS that are subsequently repaired and mutations in genetic susceptibility or cell cycle genes. It is unclear whether these mutations are directly relevant to the pathogenesis of MMs. Epigenetic changes during carcinogenesis may be critical to silencing of tumor suppressor genes.

Modified from Heintz et al.²²