By Luciano Marinelli
Asbestos is a natural mineral consisting of soft, flexible fibres which are resistant to heat, electricity and corrosion. Because of this, asbestos is an effective insulator and can be used to strengthen materials such as cement, clothing and paper. However, it has been shown that, when inhaled or ingested, it can cause a rare but aggressive cancer called mesothelioma (Asbestos, n.d.). Mesothelioma cancer attacks mesothelioma tissue and mostly affects the lining of the lungs and chest cavity, called the pleura. Pleural mesothelioma cancer is in fact the most common form, accounting for at least 75% of all mesothelioma cases (Asbestos, n.d.). Because there is still no cure, it is vital to be aware of its causes hence know how to prevent it. This review will outline the mechanisms by which asbestos causes this aggressive and still incurable cancer.
There are three main types of asbestos fibres that are used commercially – crocidolite, amosite and chrysotile. All three have been shown to be major causes of mesothelioma cancer, but considering chrysolite represents approximately 95% of the total production of all asbestos forms, this can be considered the number one trigger (Smith A.H. et al., 1996). Many studies have investigated the mechanisms behind this. In summary, asbestos fibres can migrate to the mesothelioma cells forming the pleural lining, where they become trapped. Here, they cause chronic inflammation and genetic damage, turning these cells cancerous. These will then grow uncontrollably forming a mass of plaque in the pleura, and this, together with the resulting accumulation of pleural fluid in the chest cavity, leads to breathing difficulties and other symptoms characteristic of this form of cancer (Asbestos, n.d.).
There are many factors that affect the potency of asbestos fibres, such as dimensions, durability, chemical composition and, most importantly, length. The length of the inhaled or ingested fibres is the major factor, and it has been shown that long asbestos fibres (LAFs) have a greater effect than short asbestos fibres (SAFs). LAFs are less easily phagocytosed by alveolar macrophages to be removed from the airways compared to SAFs, hence will be retained in the lungs for a longer time and, as a result, have a longer lasting and stronger effect (Boulanger G. et al., 2014). The continuously failed phagocytosis of LAFs by alveolar macrophages will trigger these cells to release reactive oxygen species (ROS), which in turn will lead to DNA damage and chronic inflammation (Gaudino G. et al., 2020).
Many studies have also proposed another mechanism that results in ROS production, in which the iron present on or around the asbestos fibres can trigger this carcinogenic process (Benedetti S. et al., 2015). Asbestos provides a surface onto which various proteins from the cytoplasm adsorb, leading to the cells shrinking onto the fibre forming asbestos bodies (Botham S.K. et al., 1968). The iron in the asbestos bodies will catalyze the formation of ROS by promoting the formation of the highly reactive OH free radical from H2O2 (Fenton reaction), which can also be triggered by the asbestos-activated macrophages in the alveoli (Hardy J.A. et al., 1995). OH and other ROS modify DNA, particularly at telomeres, as well as DNA repair proteins, resulting in DNA strand breaks and base modifications. 8-hydroxy-2’-deoxyguanosine (8OhdG) is a major product of this oxidative damage (Benedetti A. et al., 2015), and causes G🡪T and A🡪C base substitutions, which have been shown to be sites of oncogene expression, leading to cancer proliferation (Moriya M., 1993).
Moreover, exposure to asbestos causes necrosis of healthy mesothelioma cells because of the increased production of TNF-α (Yang H. et al., 2006) and HMGB1 (Gaudino G. et al., 2020). HMGB1 is a damage-associated protein (DAMP) and can be secreted into the extracellular space where it will bind to RAGE receptors on inflammatory cells such as macrophages (Pellegrini L. et al., 2017). Binding of HMGB1 to RAGE receptors will promote chronic inflammation by increasing the expression of the NLRP3 inflammasome, which in turn induces the expression of various cytokines, particularly interleukin-1β (IL-1β) (Gaudino G. et al., 2020). This inflammatory environment triggers the transformation of the remaining mesothelioma cells into carcinogenic. The subsequent activation of the NF-κB-dependent pathway promotes survival and proliferation of the malignant mesothelioma cells, allowing the cancer to spread (Nishikawa S. et al., 2014).
Carcinogenesis of the mesothelioma cells is acquired through gene mutations affecting DNA repair mechanisms (Gaudino G. et al., 2020). Mutations in the BRCA1 associated protein 1 (BAP1) gene are the most common, having been shown to be present in around 20% of mesothelioma cancer specimens (Rusch A. et al., 2015). This mutation, located at chromosome 3p21, has been shown to affect the germline and be transmitted via Mendelian autosomal dominant inheritance. This suggests mesothelioma is linked to the interaction between genes and environment (GxE interaction), rather than asbestos alone (Yoshikawa Y. et al., 2020). Support of this discovery comes from experiments performed with BAP1+/- heterozygous mice exposed to very low doses of asbestos fibres. These developed mesothelioma at a similar rate to WT BAP1 mice exposed at ten-times higher doses (Napolitano A. et al., 2016). BAP1 is mainly localized in the endoplasmic reticulum, where it deubiquitylates and stabilises the IP3R3 receptor, responsible for modulating Ca2+ release from the ER to the cytosol, from where it will move into mitochondria and cause apoptosis. Therefore, lower levels of BAP1 are associated with reduced apoptosis of malignant mesothelioma cells, hence allowing the cancer to proliferate and cause further damage (Affar E.B. et al., 2018).
Overall, asbestos is a big cause of concern for the development of malignant mesothelioma cancer. In light of the large amount of research confirming its toxicity, the use of asbestos has been banned in more than 52 countries (Baur X. et al., 2015). However, up to 1% of asbestos is still legal to use in the United States (Maacenter, n.d.), and research is showing an increasing involvement of GxE interaction, suggesting asbestos isn’t the only cause of mesothelioma. Therefore, more research has to be done to get a clearer picture on its pathogenesis, so that better treatments, as well as more effective policies regarding asbestos use, can be developed.
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