New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas

Abstract

Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.

Figure 1

Properties of chrysotile (white) asbestos. A: Image of bundle of curly chrysotile fibers before processing. B: Scanning electron micrograph of chrysotile fibers (arrows) causing deformation of red blood cells. Chrysotile is positively charged, hemolytic, and cytolytic, primarily due to its magnesium content. Leaching of magnesium renders chrysotile less toxic and also results in chrysotile fiber dissolution over time. C: Scanning electron micrograph of interaction of long chrysotile fiber with the respiratory epithelium of the alveolar duct junction after inhalation by rats. Arrowheads show points of contact with and between epithelial cells. Subsequent penetration into and between cells leads to fiber deposition in the lung interstitum and access to the visceral pleura and pleural space. D: Polarized microscopy showing chrysotile fibers and fibrils.

Figure 2

Properties of crocidolite, or blue, asbestos. A: Riebeckito ore showing veins of crocidolite asbestos fibers (arrow) before processing. B: Scanning electron micrograph showing morphology of needle-like fibers. C: Early penetration of a crocidolite fiber into the differentiated tracheobronchial epithelium in tracheal organ culture. D: Growth of metaplastic cells over long fibers of crocidolite observed at 1 month in this model. These events have not been captured in the pleura in animal inhalation models or in clinical specimens in humans, but mesothelial cells undergo proliferation, as measured by cell counts, or immunochemical markers have been observed in response to crocidolite asbestos in vitro and after inhalation by rats.

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. 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.

Figure 4

The NLRP3 (NAPL3) inflammasome is a key player in initiation of inflammation and release of chemokines and cytokines in human mesothelial cells and macrophages in response to long, pathogenic fibers. ROS appear to play a role in both activation of NADPH during phagocytosis and lysosomal degradation, which then releases asbestos fibers into the cytoplasm, where they interact with NLRP3 and induce caspase-1 activity. As a consequence, mature IL-1β, high-mobility group protein 1, and IL-1β–related cytokines are released into the tumor milieu, creating episodic bouts of cell injury, inflammation, and compensatory proliferation. Levels of these key inflammatory factors are reduced in mesothelial cells transfected with small-interfering NLRP3 and enhanced in the presence of TNF-α released by mesothelial cells, TAMs, and macrophages in the tumor environment.