Materiały źródłowe

• #1

  https://link.springer.com/article/10.1007/s11864-008-0067-z

  The incidence of mesothelioma has gone from almost none to the current 2500-3000 cases per year in the USA. […] Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. […] The capacity of asbestos to induce mesothelioma has been linked to its ability to cause the release of TNF- (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. […] Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture.

• #1 Jornal Brasileiro de Pneumologia – Malignant pleural mesothelioma: an update

  https://www.jornaldepneumologia.com.br/details/3621/en-US/malignant-pleural-mesothelioma–an-update

  Malignant mesothelioma (MM) is a rare type of cancer associated with occupational or environmental asbestos exposure in 80% of cases. […] Although the association between asbestos exposure and mesothelioma pathogenesis is widely accepted, a common hypothesis has not been reached to explain it. Up to 80% of MPM patients have been previously exposed to asbestos. However, the reason for only a small proportion of asbestos-exposed individuals develop MM (2-10%) remains unknown. […] Mesothelial cells (MC) are highly susceptible to asbestos cytotoxicity, and many pathogenic events may contribute to carcinogenesis during the long latency period between asbestos exposure and tumor development. […] The mechanisms through which inflammation affects the development of MM are not fully understood, but growing evidence has supported a link between the local and systemic inflammatory response and patient prognosis.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Mesothelioma-Pathophysiology.aspx

  The exact mechanism of how mesothelioma, which is a highly aggressive tumor with a dismal prognosis, develops remains unclear. […] The pathophysiological mechanisms responsible for mesothelioma have been linked to asbestos fibers such as curly, serpentine fibers (white asbestos), or long chain-like fibers such as amosite (brown asbestos), crocidolite (blue asbestos), anthophyllite, tremolite, and actinolite. […] During the long latency period of malignant mesothelioma, a myriad of pathogenic events may occur that can contribute to the development of the disease. After asbestos fibers are inhaled deeply into the lung and penetrate pleural space, prolonged cycles of tissue damage, repair, and local inflammation are initiated following the interaction of asbestos fibers with mesothelial cells. That, in turn, leads to carcinogenesis.

• #1 Mesothelioma – Wikipedia

  https://en.wikipedia.org/wiki/Mesothelioma

  Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. […] Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than „feathery fibers” (chrysotile or white asbestos fibers). […] However, there is now evidence that smaller particles may be more dangerous than the larger fibers. […] Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. […] It has been suggested that in humans, transport of fibers to the pleura is critical to the pathogenesis of mesothelioma. […] Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. […] The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities.

• #1 Mesothelioma Epidemiology, Carcinogenesis and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2717086/

  The incidence of mesothelioma has gone from almost none to the current 25003000 cases per year in the USA. Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. The capacity of asbestos to induce mesothelioma has been linked to it ability to cause the release of TNF- (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture. The mechanisms of asbestos carcinogenicity are not fully understood. During the long latency period of MM, many pathogenentic events may occur that can contribute to MM. Compared to other cell types tested, human mesothelial cells are very susceptible to asbestos cytotoxicity. Asbestos fibers induce toxicity in a dose-dependent manner. Recent work addressed this paradox and demonstrated a critical role for tumor necrosis factor-alpha (TNF-) and NF-B signaling in mediating responses of human mesothelial cells to asbestos. Human mesothelial cells exposed to asbestos can accumulate DNA damages. Asbestos causes DNA strand breaks mediated by iron-catalyzed free radicals. In addition, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), asbestos fibers can indirectly induce genotoxicity including base substitutions, deletions, rearrangements, insertions, sister chromatid exchanges, and chromosomal aberrations which may lead to a broad spectrum of mutations in mammalian cells. The activation of the NF-B pathway stimulated by TNF- allows mesothelial cells with asbestos-induced DNA damage to divide rather than die, and if sufficient specific genetic damage accumulates to eventually develop into a MM. In addition to TNF-, other growth factors and cytokines have been implicated in asbestos carcinogenesis and their role in MM pathogenesis is being investigated. After interaction with mesothelial cells, asbestos triggers multiple cell-signaling pathways. Crocidolite fibers can induce autophosphorylation of the epidermal growth factor receptor, which stimulates the extracellular signal regulated kinase (ERK1/2) signaling pathway. This effect in turn increases activator protein (AP)-1 activity and mitosis of mesothelial cells. Cytogenetic and loss of heterozygosity analyses of MMs have detected frequent deletions of specific regions within chromosome arms 1p, 3p, 4p, 4q, 6q, 9p, 13q, 14q, 15q and 22q. Certain tumor suppressor genes located in these chromosomal regions have also been implicated, including CDKN2A/ARF at chromosome band 9p21 and NF2 at 22q12. Mutations of the p53 gene (TP53) are occasionally observed in MMs. Loss and/or inactivation of these tumor suppressor genes may play a role in the development and progression of MM. SV40 produces two proteins that are oncogenic: Large T and small t antigens. In human MM biopsies, the large T antigen (Tag) was found to bind and inhibit p53 and pRb tumor suppressor proteins, thus contributing to MM carcinogenesis. That SV40 and asbestos might be co-carcinogens was first demonstrated by Bocchetta et al. during in vitro studies of human mesothelial cells. These observations were confirmed by Kroczynska et al., who demonstrated a strong co-carcinogenic effect between asbestos and SV40. Among different types of mineral fibers, erionite is the most potent induces of MM. Genetic susceptibility to MM was observed in the Cappadocian villages of Tuzkoy, Karain, and Old Sarihidir. Several US families have incidences of MM similar to those found in the Cappadocian families. It is possible that in the US MM families, genetic predisposition and asbestos exposure (or SV40) cause MM. MM is an aggressive malignancy caused by multiple factors that may work alone or in combination.

• #1 Causes and Pathogenesis of Malignant Mesothelioma | IntechOpen

  https://www.intechopen.com/chapters/80836

  The carcinogenesis mechanism in pleural MM is complex. Inhaled asbestos fibers move to the pleura. Fibers in the pleural space irritate the tissue, resulting in a cycle of tissue injury and repair. […] Asbestos fibers also enter mesothelial cells, interfering with mitosis, causing DNA mutations, and changing chromosome structure. […] The way erionite is thought to cause MM is by activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, which in turn triggers an autocrine feedback loop in mesothelial cells, modulated by the interleukin-1 receptor. […] The carcinogenic risk associated with exposure to ionizing radiation has been evaluated previously in the IARC monographs. […] Chronic serosal membranes inflammations can induce MM of pleura and peritoneum.

• #1 Mesothelioma – Wikipedia

  https://en.wikipedia.org/wiki/Mesothelioma

  The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial, and pleural cavities. […] Deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. […] The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. […] Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.

• #1 Frontiers | The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01366/full

  Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials. […] The inflammatory response to asbestos is a cardinal feature of mesothelioma’s pathogenesis and microenvironment. The inflammatory response to asbestos fibers that reach the outer pulmonary parenchyma is one hypothesis for how amphibole fibers and fluid enter the pleural space in the first place. In addition, mesothelial cells in contact with asbestos fibers generate CCL2, attracting macrophages which become embroiled in “frustrated phagocytosis” due to the size and biopersistence of amphibole fibers. Macrophage production of Reactive Oxygen Species (ROS) and nitrogen species augments the reactive oxygen/nitrogen species already catalyzed by the iron in asbestos fibers. The quantity of hydroxyl free radicals and nitric oxide free radicals have been associated with the extent of DNA strand breaks and gene deletions in cultured cell lines and are considered responsible for key mutagenic events.

• #1 Mesothelioma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Mesothelioma_pathophysiology

  Asbestos causes DNA damage directly by mechanically interfering with the segregation of chromosomes during mitosis and indirectly by inducing mesothelial cells and macrophages, to release mutagenic reactive oxygen and nitrogen species. Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma. […] Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.

• #1 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  A crucial role in this process is recognized to the pleural macrophages recruited at the inflammatory site, which, failing the attempts to eliminate the fibers, are subject to frustrated phagocytosis, a process leading to activation of Nicotinamide adenine dinucleotide phosphate (NADPH), the generation of reactive oxygen species (ROS) and release of proinflammatory molecules (IL-1β, IL-8, IL-6 and TNF-α). […] Accumulation of asbestos fibers leads to aberrant activation of intracellular pathways and transcriptional processes responsible for the malignant transformation of mesothelial cells and the development of a unique inflammatory microenvironment. […] Indeed, tumor-associated macrophages (TAMs), T regulatory cells (Treg), such as cancer-associated fibroblasts (CAFs), are the most abundant population of MPM infiltration, that, in response to pro-tumoral signals, acquire malignant and immunosuppressive properties, influencing the progression of the tumor.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Mesothelioma-Pathophysiology.aspx

  The long latency period between asbestos exposure and the development of mesothelioma, which can be up to 40 years, suggests that multiple genetic alterations are important in the conversion of normal cells to malignant mesothelial cells. […] Asbestos fibers are also engulfed by mesothelial cells, which can disrupt mitotic spindles and influence the cell cycle process. […] The loss of one copy of chromosome 22 represents the single most consistent chromosomal change in patients with mesothelioma. […] Certain tumor suppressor genes located in the aforementioned chromosomal regions have also been implicated in the disease, including CDKN2A/ARF at chromosome band 9p21 and NF2 at 22q12. […] It has also been postulated that simian virus 40 (SV40) can bind to and inactivate wild-type p53 in mesothelioma, thus interfering with DNA repair, as well as apoptotic and growth inhibitory functions.

• #1 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  MPM is characterized by a low tumor mutation burden (TMB), uncommon genetic aberrations, and recurrent somatic mutations in tumor suppressor genes, in both asbestos and non-asbestos induced tumors. […] The deletion of this gene affected the cell cycle regulating function of pRB and p53. […] For its proximity to CDKN2A, the methylthioadenosine phosphorylase (MTAP) gene is frequently co-deleted in different cancer types, including malignant mesothelioma. […] Other common mutations in mesothelioma are in chromosome 3, involving the loss of the BAP1 gene, in chromosome 22 enclosing the neurofibromin2 (NF2) gene, and in TP53. […] BAP-1 loss, together with MTAP/CDKN2A deletion, has been recently proposed as useful markers to improve the diagnostic sensitivity for MPM. […] Different from other cancers, driver mutations have not been found in mesothelioma and the pathogenesis of this cancer is undoubtedly related principally to the inflammatory microenvironment created by asbestos deposition in the pleura that stimulates the immune response.

• #1 Mesothelioma – Wikipedia

  https://en.wikipedia.org/wiki/Mesothelioma

  Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms. […] Several genes are commonly mutated in mesothelioma, and may be prognostic factors. […] These include primarily BAP1, NF2, and TP53; epidermal growth factor receptor (EGFR) and C-Met, receptor tyrosine kinases can also be altered and overexpressed in many mesotheliomas. […] In general, mesothelioma is characterized by loss of function in tumor suppressor genes, rather than by an overexpression or gain of function in oncogenes. […] As an environmentally triggered malignancy, mesothelioma tumors have been found to be polyclonal in origin, by performing an X-inactivation based assay on epitheloid and biphasic tumors obtained from female patients. […] These results suggest that an environmental factor, most likely asbestos exposure, may damage and transform a group of cells in the tissue, resulting in a population of tumor cells that are, albeit only slightly, genetically different.

• #1 Mesothelioma – Wikipedia

  https://en.wikipedia.org/wiki/Mesothelioma

  In general, asbestos fibers are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages. […] Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. […] This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. […] The most common abnormality is monosomy of chromosome 22. […] Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p, and 6q chromosome arms. […] Asbestos has also been shown to mediate the entry of foreign DNA into target cells.

• #1 How asbestos and other fibers cause mesothelioma – Gaudino – Translational Lung Cancer Research

  https://tlcr.amegroups.org/article/view/36019/html

  Chronic inflammation plays a major role in the pathogenesis and tumorigenesis induced by asbestos and other carcinogenic mineral fibers. […] The role of HMGB1 and related chronic inflammation is supported by the report on the preventative role of aspirin for mesothelioma, targeting HMGB1 activities and inflammation, and on the antitumor activity of aspirin in mesothelioma xenograft models. […] The current approach adopted in the field of carcinogens is to combine genetics and environmental studies to study GxE interactions. […] The mechanisms of cellular transformation following the exposure of HM to carcinogenic mineral fibers was elucidated by the discovery of the role of chronic inflammation mediated by HMGB1 and the inflammasome. Moreover, the identification of BAP1 as a main controller of cell death and metabolism contributed to the definition of the complex array of molecular events mediated by asbestos carcinogenesis.

• #1 Jornal Brasileiro de Pneumologia – Malignant pleural mesothelioma: an update

  https://www.jornaldepneumologia.com.br/details/3621/en-US/malignant-pleural-mesothelioma–an-update

  The presence of an intense and sustained systemic inflammatory response characterized by leukocyte migration and cytokine secretion promotes malignant transformation of MC. […] Crocidolite causes the accumulation of macrophages in the pleura and lung, which, in turn, release TNFA. […] The activation of the NF-kB pathway by TNFA allows MCs bearing asbestos-induced DNA damage to eventually evolve into MM. […] Therefore, part of the pathogenetic mechanism of asbestos fibers is thought to be associated with their persistence in the pleura over long periods of time triggering repeated cycles of lesion/repair at the inflammation site.

• #1 Jornal Brasileiro de Pneumologia – Malignant pleural mesothelioma: an update

  https://www.jornaldepneumologia.com.br/details/3621/en-US/malignant-pleural-mesothelioma–an-update

• #1 How asbestos and other fibers cause mesothelioma – Gaudino – Translational Lung Cancer Research

  https://tlcr.amegroups.org/article/view/36019/html

  Mesothelioma has long been associated with the exposure to asbestos, which was largely used in manufacturing activities. Toxicology studies in vitro and in vivo demonstrated that asbestos fibers were carcinogenic, and epidemiology studies revealed that asbestos exposure was paralleled by the increase in the incidence of mesothelioma and related mortality rates. […] More recently, the role of chronic inflammation and the molecular mechanisms involved in carcinogenesis by mineral fibers were elucidated following the discovery of the roles of HMGB1 and inflammasome. A change of paradigm was the discovery of a prevalence of mesotheliomas attributable to inherited mutations of cancer susceptibility genes. […] The mechanisms of asbestos carcinogenesis have been elusive for long time and the initial hypothesis of the fiber mechanical interference with cell division has been definitely ruled out. However, some studies suggested that fiber chemical structure may play a role and iron in particular, as impurity or even as a chemical component of the fiber structure, has been taken into consideration to explain the carcinogenic process induced by asbestos.

• #1 The Role of HMGB1 in the Pathogenesis of Mesothelioma – Haining Yang

  https://grantome.com/grant/NIH/R01-CA160715-04

  The data suggest that HMGB1 may be the „master switch” by which the chronic inflammation necessary for asbestos-induced MM is initiated. […] However, the precise mechanism(s) by which HMGB1 induces the release of TNF-alpha and induces transformation of mesothelial cells is unknown. […] We hypothesize that upon asbestos exposure, the HMGB1-induced inflammatory response is essential to transformation of HM into MM via NF-kB signaling, that HMGB1 is necessary for maintaining the malignant cell phenotype and that inhibition of HMGB1 may be used to prevent or treat MM. […] To accomplish these aims, we will use both in vitro and in vivo models and determine whether HMGB1 inhibitors prevent the secretion of inflammatory molecules, which HMGB1 receptor(s) play a critical role in transformation of HM cells, whether HMGB1 activates NF-kB signaling and whether specific inhibition of HMGB1 reduces asbestos-induced inflammation and either prevents MM.

• #1 Recent progress and perspectives on the mechanisms underlying Asbestos toxicity | Genes and Environment | Full Text

  https://genesenvironment.biomedcentral.com/articles/10.1186/s41021-021-00215-0

  Long asbestos fibers that reach the pleura are retained for extended periods of time and cause prolonged inflammation due to frustrated phagocytosis. […] The activated NLRP3 inflammasome induces the secretion of IL-1. […] Inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are capable of causing DNA damage. […] The BAP1 protein is a deubiquitylase that modulates the activity of multiple genes and proteins that control DNA replication, DNA repair, metabolism, and cell death. […] Carbone et al. proposed a model that could explain the paradox of asbestos carcinogenicity. First, the phagocytosed asbestos in macrophages may cause a mutagenic microenvironment rich in ROS and HMGB1, enhancing mutations in mesothelial cells. Then, BAP1-mutated mesothelial cells may escape cell death and accumulate further DNA damage (CDKN2A, NF2, TP53, LATS2, SETD2), leading to carcinogenesis.

• #1 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  Malignant pleural mesothelioma has a unique and complex tumor microenvironment. […] Several reports underlined the key role of immune and stromal cells in tumorigenesis and progression of mesothelioma. […] These non-cancer cells, via a reciprocal informational exchange with tumor cells, established a chronic inflammatory microenvironment that support the malignancy and the chemoresistant phenotype of the tumor. […] The knowledge of the cellular and molecular mechanisms underlying tumor microenvironment interconnection was recently considered a crucial point for the design of more effective therapeutic strategies. […] MPM pathogenesis has unique features because it is mainly related to the exposure of external carcinogens that are mostly represented by asbestos fibers. […] Despite the efforts to limit asbestos use, it is actually banned in 30% of countries.

• #1 Frontiers | The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01366/full

  In summary, the innate immune system, particularly macrophages, contribute to a milieu that promotes mutagenesis as well as the survival of mutated mesothelial cells. […] In mesothelioma, the surrounding stroma is not merely a scaffold but promotes tumor growth, invasion and protection from an anti-tumor immune response. Many genes related to the synthesis of, and interaction with, extracellular matrix (ECM) are upregulated in RNA expression analyses of mesothelioma specimens. These ECM-related genes are more associated with biphasic, desmoplastic and sarcomatoid variants—the histological subtypes with poorer prognoses. […] Furthermore, the stroma and stromal cells provide a scaffold for invasion, a barrier to the immune response and stimulate tumor growth and the differentiation of immunosuppressive cells. […] While checkpoint inhibition represents an exciting development in the treatment of several solid tumors, the outcomes in mesothelioma have been less positive and may well be affected by the complex structure of the tumor microenvironment in mesothelioma.

• #1 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  Tumor cells have developed different mechanisms to escape immune surveillance, such as the activation of inhibitory pathway (PD-1/PD-L1) leading to T-cell exhaustion and suppression of cytotoxicity. […] Overexpression of PD-L1 on immune cells and PD-1 of tumoral-origin was also described in MPM. […] Given the importance of the interactions between the surrounding and neoplastic cells, several research groups have investigated the content of TME in terms of cellular component and exchanged soluble factors with the aim to improve the immunotherapy. […] The inflammatory landscape of mesothelioma TME is required to be deeply investigated in order to restore the immune response and develop strategies with better therapeutic benefits.

• #1 The pathogenesis of mesothelioma is driven by a dysregulated translatome

  https://eprints.gla.ac.uk/248582/

  Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. […] The disease primarily results from loss of tumour suppressor gene function and there are no druggable driver oncogenes associated with MpM. […] We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. […] This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. […] These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. […] Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. […] Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.

• #1 The pathogenesis of mesothelioma is driven by a dysregulated translatome | Nature Communications

  https://www.nature.com/articles/s41467-021-25173-7

  Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. […] These data suggest that targeting mRNA translation could provide a viable, alternative treatment route for this incurable disease. […] We also demonstrate that combined mTORC1 and 2 inhibition impacts on cell growth of cultured and ex vivo tumour tissue and significantly extends the survival of mice with asbestos-induced mesothelioma. […] Our data suggest that treatment with these drugs by targeting both mitochondrial fission/fusion and the selective synthesis of nuclear-encoded mitochondrial proteins and components of the canonical translation machinery reduces aberrant cell growth and leads to lifespan extension.

• #1 Causes and Pathogenesis of Malignant Mesothelioma | IntechOpen

  https://www.intechopen.com/chapters/80836

  Malignant mesothelioma (MM) is a malignancy that arises from the mesothelium, a thin layer of tissue that covers the body’s serous cavities, such as the pleural, peritoneal, pericardial, and tunica vaginalis of the testis. […] The involvement of asbestos, other mineral fibers, nanotechnological products, the simian virus SV40, ionizing radiation, genetic factors, and inflammation in the development of MM has been discussed in this chapter. This study focuses on the role of other mineral fibers, such as erionite, fluoroedenite, balangeroite, and carbon nanotubes, as well as genetic mutations in BAP1 and other genes, in the pathogenesis of MM. […] The pathogenesis of MM is thought to be multifactorial and a better understanding of the pathogenetic mechanisms may enable the identification of efficient and personalized treatment patterns for precision medicine.

• #1 The pathogenesis of mesothelioma – PubMed

  https://pubmed.ncbi.nlm.nih.gov/11836664/

  About 80% of malignant mesotheliomas (MM) in the Western World develop in individuals with higher than background exposure to asbestos. Only a fraction of those exposed to asbestos develop mesothelioma, indicating that additional factors play a role. Simian virus 40 (SV40), a DNA tumor virus that preferentially causes mesothelioma in hamsters, has been detected in several human mesotheliomas. The expression of the SV40 large tumor antigen in mesothelioma cells, and not in nearby stromal cells, and the capacity of antisense T-antigen treatment to arrest mesothelioma cell growth in vitro suggest that SV40 contributes to tumor development. The capacity of T-antigen to bind and inhibit cellular p53 and retinoblastoma (Rb)-family proteins in mesothelioma, together with the very high susceptibility of human mesothelial cells to SV40-mediated transformation in vitro, supports a causative role of SV40 in the pathogenesis of mesothelioma.

• #1 Risk Factors for Mesothelioma | American Cancer Society

  https://www.cancer.org/cancer/types/malignant-mesothelioma/causes-risks-prevention/risk-factors.html

  Some studies have raised the possibility that infection with simian virus 40 (SV40) might increase the risk of developing mesothelioma. But most experts agree that at this time we still dont know if SV40 is responsible for some mesotheliomas. This important topic is still being researched. […] A mutation or change in the gene called BAP1 can be passed in families and has been linked to mesothelioma. But BAP1 mutations are rare.

• #1 The pathogenesis of mesothelioma – PubMed

  https://pubmed.ncbi.nlm.nih.gov/11836664/

  Asbestos appears to increase SV40-mediated transformation of human mesothelial cells in vitro, suggesting that asbestos and SV40 may be cocarcinogens. […] Mesothelioma appears to have a complex etiology in which environmental carcinogens (asbestos and erionite), ionizing radiation, viruses, and genetic factors act alone or in concert to cause malignancy.

• #1 SciELO Brazil – Malignant pleural mesothelioma: an update Malignant pleural mesothelioma: an update

  https://www.scielo.br/j/jbpneu/a/f6Vk7bFyzjZTStkn9r5s4HD/?lang=en

  Tumor necrosis factor-alpha (TNFA) and nuclear factor-kB (NF-kB) signaling were also involved in MC response to asbestos. Crocidolite causes the accumulation of macrophages in the pleura and lung, which, in turn, release TNFA. Crocidolite also induces MC to express the TNFA receptor, TNF-R1, as well as to secrete TNFA (thus causing paracrine and autocrine responses). The activation of the NF-kB pathway by TNFA allows MCs bearing asbestos-induced DNA damage to eventually evolve into MM. In fact, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), whose production is catalyzed by iron, asbestos fibers can induce genotoxicity indirectly, which may lead to a wide spectrum of mutations. Therefore, part of the pathogenetic mechanism of asbestos fibers is thought to be associated with their persistence in the pleura over long periods of time triggering repeated cycles of lesion/repair at the inflammation site. Indeed, the presence of inflammatory cells in the tumor is a prognostic factor.

• #1 SciELO Brazil – Malignant pleural mesothelioma: an update Malignant pleural mesothelioma: an update

  https://www.scielo.br/j/jbpneu/a/f6Vk7bFyzjZTStkn9r5s4HD/?lang=en

  Although the association between asbestos exposure and mesothelioma pathogenesis is widely accepted, a common hypothesis has not been reached to explain it. Up to 80% of MPM patients have been previously exposed to asbestos. However, the reason for only a small proportion of asbestos-exposed individuals develop MM (2-10%) remains unknown. […] Molecular mechanisms associated with MM pathogenesis. Inhaled asbestos fibers transverse terminal airways and lodge themselves in the pleural space. Macrophages try to phagocytize these fibers without effect and in doing that they release reactive oxygen species and reactive nitrogen species, which may promote genotoxic damage, and recruit other inflammatory and immune cells. Repeated DNA damage by ROS and RNS may lead to the accumulation of oncogenic mutations in the mesothelial cells. The genes most frequently mutated in mesothelioma and that may be associated with malignant transformation of mesothelial cells are involved with DNA repair, the Hippo pathway, cell cycle control, DNA methylation and the mTOR pathway. Germ line mutations in genes associated with DNA repair (BAP1, BRCA1, CHECK2, etc) are found in 12% of mesothelioma patients and are associated with earlier disease onset and good prognosis. In parallel, the inflammatory mediators released in the microenvironment may promote cell survival (inhibiting apoptotic signals) and stimulate mesothelial cell proliferation (even in the presence of DNA damage), activate fibroblast to produce extracellular matrix proteins, and promote neoangiogenesis. These modifications favor tumor growth and create an immunosuppressive milieu.

• #1 Mesothelioma Pathogenesis

  http://www.mesothelioma-mesothelioma.com/pathogenesis.htm

  The pathogenesis of mesothelioma in humans is predicated on the transport of asbestos fibers to the pleura of the lungs the fluid-filled sac that surrounds the lungs. These fibers induce an immune system response, by macrophages and other specialized cells, to the lesions that occur as a result of asbestos-fiber irritation of tissues. These lesions continue to attract, and aggregate, specialized cells, causing cellular changes within the lesion that terminate in a malignant tumor. […] Evidence gathered from animal experiments indicates that asbestos acts as a complete carcinogen, though the molecular mechanisms of malignancy are not entirely clear. However, research indicates that asbestos fibers act directly on chromosomes, or structural proteins within the cell wall, to effect complex changes, with chromosome 22 showing the most distinct changes. These changes can lead to either deletion of tumor suppressing genes or the prevention of apoptosis (programmed cell death) or activation of oncogenes, via the interposition of foreign DNA, which asbestos appears to facilitate.

• #1 Malignant pleural mesothelioma: new mechanism of spread discovered

  https://www.meduniwien.ac.at/web/en/about-us/news/detailsite/2018/news-im-dezember-2018/malignant-pleural-mesothelioma-new-mechanism-of-spread-discovered/

  Malignant pleural mesothelioma is divided into three subtypes, one of which is particularly aggressive. Researchers from the Comprehensive Cancer Center (CCC) of MedUni Vienna and Vienna General Hospital have now managed to discover a mechanism that contributes to this aggressive behaviour: the tumour cells of this subtype are able to assume special characteristics that promote migration and therefore spread of the cancer. […] This is possible because the cells receive the requisite signals for this spread from certain messenger substances, namely the two growth factors FGF2 and EGF. By blockading these signals, it might be possible to develop new approaches for treating this subtype of malignant pleural mesothelioma. […] The researchers found that, in aggressive malignant pleural mesothelioma, EMT is triggered by defined signals. These are, in fact, a group of so-called fibroblast growth factors (FGF2) and epidermal growth factors (EGF). These signaling substances bind to receptors on the surface of the tumour cells and forward the signal to modify into the cell interior.

• #1 Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02050-1

  Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism. […] Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options. […] The mechanism underlying the pathogenesis of MPM remains unclear. Based on our previous research findings showing that COX-2 and PGE2 contribute to the tumorigenicity of MPM, this study highlights the stimulating action exerted by COX-2 on the expression of CYP19A1 in MPM in order to better understand the pathways linking chronic inflammation associated with oncogenic transformation, consequently opening new preventive and therapeutic strategies for MPM. […] The results indicate pAKT as a critical pathway in the interaction between COX-2 and CYP19A1 forming a positive loop that fuels the pathogenesis of MPM.

• #1 Malignant Mesothelioma: Global Incidence and Relationship with Asbestos

  https://www.jstage.jst.go.jp/article/indhealth/45/3/45_3_379/_article

  Mesothelioma incidence varies markedly from one country to another. […] A lot of data indicate a relationship between mesothelioma and asbestos. […] The latency periods elapsing between first exposure to asbestos and development of mesothelioma are mostly longer than 40 yr. […] An inverse relationship exists between intensity of asbestos exposure and length of the latency period. […] Mesothelioma generally develops after long-time exposures to asbestos. […] Some recent studies show that the risk increases with the duration of exposure. […] Possible co-factors in the pathogenesis of asbestos-related mesothelioma include genetic predisposition, diets poor in fruit and vegetables, viruses, immune impairment, recurrent serosal inflammation. […] The study of co-morbidity in mesothelioma could give an insight into the pathogenesis of the tumor.

• #1 Risk Factors for Mesothelioma | American Cancer Society

  https://www.cancer.org/cancer/types/malignant-mesothelioma/causes-risks-prevention/risk-factors.html

  The main risk factor for pleural mesothelioma is exposure to asbestos. In fact, most cases of pleural mesothelioma have been linked to high levels of asbestos exposure, usually in the workplace. […] When asbestos fibers in the air are inhaled, they can get into the lungs. Fibers that stay in the lungs can travel to the ends of the small airways and enter the pleural lining of the lung and chest wall. These fibers can then injure the cells of the pleura, and, over time, cause mesothelioma. […] The risk of developing mesothelioma is loosely related to how much asbestos a person is exposed to and how long exposure lasts. People exposed at an early age, for a long time, and at higher levels are more likely to develop this cancer. […] Mesotheliomas related to asbestos exposure take a long time to develop. The time between the first asbestos exposure and diagnosis of mesothelioma is usually between 20 and 50 years. And the risk of mesothelioma does not go down over time after the exposure to asbestos stops. The risk appears to be lifelong.

• #1 GFPT2: A novel biomarker in mesothelioma for diagnosis and prognosis and its molecular mechanism in malignant progression | British Journal of Cancer

  https://www.nature.com/articles/s41416-024-02830-4

  Mesothelioma (MESO) is an insidious malignancy with a complex diagnosis and a poor prognosis. Our study unveils Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) as a valuable diagnostic and prognostic marker for MESO, exploring its role in MESO pathogenesis. […] The role of GFPT2 in the malignant progression of MESO was investigated through in vitro and in vivo experiments. The activation of NF-B-p65 through O-GlcNAcylation at Ser75 was elucidated using experiments like HPLC-QTRAP-MS/MS and mass spectrometry analysis. […] Through rigorous verification, we have confirmed that elevated GFPT2 levels drive malignant proliferation, invasiveness, and metastasis in MESO. At the molecular level, GFPT2 augments p65 O-GlcNAcylation, orchestrating its nuclear translocation and activating the NF-B signalling pathway.

• #2 Mesothelioma Epidemiology, Carcinogenesis and Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2717086/

  The incidence of mesothelioma has gone from almost none to the current 25003000 cases per year in the USA. Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. The capacity of asbestos to induce mesothelioma has been linked to it ability to cause the release of TNF- (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture. The mechanisms of asbestos carcinogenicity are not fully understood. During the long latency period of MM, many pathogenentic events may occur that can contribute to MM. Compared to other cell types tested, human mesothelial cells are very susceptible to asbestos cytotoxicity. Asbestos fibers induce toxicity in a dose-dependent manner. Recent work addressed this paradox and demonstrated a critical role for tumor necrosis factor-alpha (TNF-) and NF-B signaling in mediating responses of human mesothelial cells to asbestos. Human mesothelial cells exposed to asbestos can accumulate DNA damages. Asbestos causes DNA strand breaks mediated by iron-catalyzed free radicals. In addition, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), asbestos fibers can indirectly induce genotoxicity including base substitutions, deletions, rearrangements, insertions, sister chromatid exchanges, and chromosomal aberrations which may lead to a broad spectrum of mutations in mammalian cells. The activation of the NF-B pathway stimulated by TNF- allows mesothelial cells with asbestos-induced DNA damage to divide rather than die, and if sufficient specific genetic damage accumulates to eventually develop into a MM. In addition to TNF-, other growth factors and cytokines have been implicated in asbestos carcinogenesis and their role in MM pathogenesis is being investigated. After interaction with mesothelial cells, asbestos triggers multiple cell-signaling pathways. Crocidolite fibers can induce autophosphorylation of the epidermal growth factor receptor, which stimulates the extracellular signal regulated kinase (ERK1/2) signaling pathway. This effect in turn increases activator protein (AP)-1 activity and mitosis of mesothelial cells. Cytogenetic and loss of heterozygosity analyses of MMs have detected frequent deletions of specific regions within chromosome arms 1p, 3p, 4p, 4q, 6q, 9p, 13q, 14q, 15q and 22q. Certain tumor suppressor genes located in these chromosomal regions have also been implicated, including CDKN2A/ARF at chromosome band 9p21 and NF2 at 22q12. Mutations of the p53 gene (TP53) are occasionally observed in MMs. Loss and/or inactivation of these tumor suppressor genes may play a role in the development and progression of MM. SV40 produces two proteins that are oncogenic: Large T and small t antigens. In human MM biopsies, the large T antigen (Tag) was found to bind and inhibit p53 and pRb tumor suppressor proteins, thus contributing to MM carcinogenesis. That SV40 and asbestos might be co-carcinogens was first demonstrated by Bocchetta et al. during in vitro studies of human mesothelial cells. These observations were confirmed by Kroczynska et al., who demonstrated a strong co-carcinogenic effect between asbestos and SV40. Among different types of mineral fibers, erionite is the most potent induces of MM. Genetic susceptibility to MM was observed in the Cappadocian villages of Tuzkoy, Karain, and Old Sarihidir. Several US families have incidences of MM similar to those found in the Cappadocian families. It is possible that in the US MM families, genetic predisposition and asbestos exposure (or SV40) cause MM. MM is an aggressive malignancy caused by multiple factors that may work alone or in combination.

• #2 Malignant pleural mesothelioma: an epidemiological perspective – Robinson- Annals of Cardiothoracic Surgery

  https://www.annalscts.com/article/view/1053/1582

  Malignant mesothelioma is a tumour arising from the mesothelial lining of the pleura, peritoneum, pericardium and tunica vaginalis. […] The association of mesothelioma with asbestos exposure is well established, with an aetiological fraction above 80%. […] The DNA virus, Simian virus 40 (SV40), has been associated with malignant mesothelioma and has been suggested as a causal co-factor. […] The latency of mesothelioma, that is the time elapsed between first exposure to asbestos and the diagnosis of disease, is long. […] Although short or low-level asbestos exposures have been linked to the development of mesothelioma, the risk of disease demonstrates dose dependence. […] The evidence has been deemed sufficient by the World Health Organisation (WHO) to conclude that all types of asbestos cause cancer in humans.

• #2 Mesothelioma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Mesothelioma_pathophysiology

  The pathogenesis of mesothelioma is influenced by the following factors: Asbestos fibres, Radiation therapy, Smoking. […] Asbestos fibres play the following role in the development of mesothelioma: The most common type of fibres found in US are the serpentine fibers, which are considered less carcinogenic than the amphibole ones. Following inhalation from the environment, these fibres are trapped in the lower third zone of the lung. They are phagocytosed by the mesothelial cells and initiate an oncogenic cascade of events which include: Activation of c-Myc and c-Jun oncogene, Promotion of antiapoptotic genes such as Bcl-xL, Binding with epidermal growth factor receptor (EGFR). […] Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in-vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis, and significantly reduce lymphokine-activated killer cell viability and recovery.

• #2 Mesothelioma – Wikipedia

  https://en.wikipedia.org/wiki/Mesothelioma

  In general, asbestos fibers are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages. […] Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. […] This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. […] The most common abnormality is monosomy of chromosome 22. […] Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p, and 6q chromosome arms. […] Asbestos has also been shown to mediate the entry of foreign DNA into target cells.

• #2 Recent progress and perspectives on the mechanisms underlying Asbestos toxicity | Genes and Environment | Full Text

  https://genesenvironment.biomedcentral.com/articles/10.1186/s41021-021-00215-0

  Long asbestos fibers that reach the pleura are retained for extended periods of time and cause prolonged inflammation due to frustrated phagocytosis. […] The activated NLRP3 inflammasome induces the secretion of IL-1. […] Inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are capable of causing DNA damage. […] The BAP1 protein is a deubiquitylase that modulates the activity of multiple genes and proteins that control DNA replication, DNA repair, metabolism, and cell death. […] Carbone et al. proposed a model that could explain the paradox of asbestos carcinogenicity. First, the phagocytosed asbestos in macrophages may cause a mutagenic microenvironment rich in ROS and HMGB1, enhancing mutations in mesothelial cells. Then, BAP1-mutated mesothelial cells may escape cell death and accumulate further DNA damage (CDKN2A, NF2, TP53, LATS2, SETD2), leading to carcinogenesis.

• #2 Reactive oxygen species a double-edged sword for mesothelioma | Oncotarget

  https://www.oncotarget.com/article/4253/text/

  It is well known that oxidative stress can lead to chronic inflammation which, in turn, could mediate most chronic diseases including cancer. […] Oxidants have been implicated in the activity of crocidolite and amosite, the most powerful types of asbestos associated to the occurrence of mesothelioma. […] Chronic inflammation triggered by asbestos exposure leads to increased production of ROS from inflammatory cells, or alteration of immunocompetent cells and later reduction of tumor immunity. […] Free radicals generated from asbestos fibers and/or damages by fibers can alter biological macromolecules including proteins, cell membrane lipids, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) resulting in the initiation of numerous signal transduction pathways that are linked to inflammation, malignant transformation, proliferation, and apoptosis.

• #2 Mesothelioma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Mesothelioma_pathophysiology

  Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor- (TGF-) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres. […] Smoking has a synergistic effect on asbestos fibre inhalation in the pathogenesis of mesothelioma. […] Development of mesothelioma is the result of multiple genetic mutations. […] Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis, by several possible mechanisms: Inactivation of tumor suppressor genes, Activation of oncogenes, Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region, Activation of DNA repair enzymes, which may be prone to error, Activation of telomerase, Prevention of apoptosis.

• #2 Jornal Brasileiro de Pneumologia – Malignant pleural mesothelioma: an update

  https://www.jornaldepneumologia.com.br/details/3621/en-US/malignant-pleural-mesothelioma–an-update

  The presence of an intense and sustained systemic inflammatory response characterized by leukocyte migration and cytokine secretion promotes malignant transformation of MC. […] Crocidolite causes the accumulation of macrophages in the pleura and lung, which, in turn, release TNFA. […] The activation of the NF-kB pathway by TNFA allows MCs bearing asbestos-induced DNA damage to eventually evolve into MM. […] Therefore, part of the pathogenetic mechanism of asbestos fibers is thought to be associated with their persistence in the pleura over long periods of time triggering repeated cycles of lesion/repair at the inflammation site.

• #2 Risk Factors for Mesothelioma | American Cancer Society

  https://www.cancer.org/cancer/types/malignant-mesothelioma/causes-risks-prevention/risk-factors.html

  The main risk factor for pleural mesothelioma is exposure to asbestos. In fact, most cases of pleural mesothelioma have been linked to high levels of asbestos exposure, usually in the workplace. […] When asbestos fibers in the air are inhaled, they can get into the lungs. Fibers that stay in the lungs can travel to the ends of the small airways and enter the pleural lining of the lung and chest wall. These fibers can then injure the cells of the pleura, and, over time, cause mesothelioma. […] The risk of developing mesothelioma is loosely related to how much asbestos a person is exposed to and how long exposure lasts. People exposed at an early age, for a long time, and at higher levels are more likely to develop this cancer. […] Mesotheliomas related to asbestos exposure take a long time to develop. The time between the first asbestos exposure and diagnosis of mesothelioma is usually between 20 and 50 years. And the risk of mesothelioma does not go down over time after the exposure to asbestos stops. The risk appears to be lifelong.

• #2 KEGG DISEASE: Malignant pleural mesothelioma

  https://www.genome.jp/dbget-bin/www_bget?ds:H00015

  Malignant mesothelioma (MM) is a rare but very aggressive tumor that arises from mesothelial cells lining the pleural, peritoneal and pericardial cavities. […] Past asbestos exposure represents the major risk factor for MPM, as the link between asbestos fibres and MPM has been largely proved by epidemiological and experimental studies. […] Recently, simian virus 40 (SV40) has been implicated in the aetiology of MPM. […] The accumulation of numerous clonal chromosomal deletions in most MMs suggests a multistep process of tumorigenesis, characterized by the loss and/or inactivation of multiple tumor suppressor genes (TSGs). […] Cytogenetic and loss of heterozygosity (LOH) analyses of MMs have demonstrated frequent deletions of specific sites within chromosome arms 1p, 3p, 6q, 9p, 13q, 15q, and 22q. […] Furthermore, TSGs within two of these regions, i.e., p16/CDKN2A-p14ARF at 9p21 and NF2 at 22q12, are frequently altered in MMs. […] Mutations of the p53 gene (TP53) are occasionally observed in MMs.

• #2 Mesothelioma: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/280367-overview

  Interleukin-8 has direct growth-potentiating activity in mesothelial cell lines. Malignant mesothelioma has also been linked to therapeutic radiation using thorium dioxide and zeolite, a silicate in the soil. […] An etiologic role for simian virus 40 in malignant mesothelioma has been suggested. However, although asbestos exposure alone has been associated with malignant mesothelioma, simian virus 40 alone has not. Thus, some epidemiologic evidence exists that simian virus 40 is a possible cocarcinogen. Its direct role at this point is still controversial. […] Most malignant mesotheliomas have complex karyotypes, with extensive aneuploidy and the rearrangement of many chromosomes. […] Loss of 1 copy of chromosome 22 is the single most common karyotypic change in malignant mesothelioma. Other chromosomal changes commonly observed include deletions in the chromosome arms 1p, 3p, 9p, and 6q. Several changes in the tumor suppressor genes p16 (CDKN2A) and p14 (ARF) and loss of function of neurofibromin-2 (NF2) have also been noted.

• #2 SciELO Brazil – Malignant pleural mesothelioma: an update Malignant pleural mesothelioma: an update

  https://www.scielo.br/j/jbpneu/a/f6Vk7bFyzjZTStkn9r5s4HD/?lang=en

  Tumor necrosis factor-alpha (TNFA) and nuclear factor-kB (NF-kB) signaling were also involved in MC response to asbestos. Crocidolite causes the accumulation of macrophages in the pleura and lung, which, in turn, release TNFA. Crocidolite also induces MC to express the TNFA receptor, TNF-R1, as well as to secrete TNFA (thus causing paracrine and autocrine responses). The activation of the NF-kB pathway by TNFA allows MCs bearing asbestos-induced DNA damage to eventually evolve into MM. In fact, by causing the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS), whose production is catalyzed by iron, asbestos fibers can induce genotoxicity indirectly, which may lead to a wide spectrum of mutations. Therefore, part of the pathogenetic mechanism of asbestos fibers is thought to be associated with their persistence in the pleura over long periods of time triggering repeated cycles of lesion/repair at the inflammation site. Indeed, the presence of inflammatory cells in the tumor is a prognostic factor.

• #2 SciELO Brazil – Malignant pleural mesothelioma: an update Malignant pleural mesothelioma: an update

  https://www.scielo.br/j/jbpneu/a/f6Vk7bFyzjZTStkn9r5s4HD/?lang=en

  Mesothelial cells (MC) are highly susceptible to asbestos cytotoxicity, and many pathogenic events may contribute to carcinogenesis during the long latency period between asbestos exposure and tumor development. MC is affected by various cellular changes induced by asbestos, such as DNA damage, cell cycle inhibition, and apoptosis. Conversely, MC produces many inflammatory mediators in response to asbestos. […] The mechanisms through which inflammation affects the development of MM are not fully understood, but growing evidence has supported a link between the local and systemic inflammatory response and patient prognosis. The presence of an intense and sustained systemic inflammatory response characterized by leukocyte migration and cytokine secretion promotes malignant transformation of MC. Malignant cells attract myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory lymphocytes (Treg). These cells potentiate tumor development and promote immune escape, extracellular matrix remodeling, and angiogenesis.

• #2 Causes and Pathogenesis of Malignant Mesothelioma | IntechOpen

  https://www.intechopen.com/chapters/80836

  The carcinogenesis mechanism in pleural MM is complex. Inhaled asbestos fibers move to the pleura. Fibers in the pleural space irritate the tissue, resulting in a cycle of tissue injury and repair. […] Asbestos fibers also enter mesothelial cells, interfering with mitosis, causing DNA mutations, and changing chromosome structure. […] The way erionite is thought to cause MM is by activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, which in turn triggers an autocrine feedback loop in mesothelial cells, modulated by the interleukin-1 receptor. […] The carcinogenic risk associated with exposure to ionizing radiation has been evaluated previously in the IARC monographs. […] Chronic serosal membranes inflammations can induce MM of pleura and peritoneum.

• #2 Frontiers | The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

  https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01366/full

  In summary, the innate immune system, particularly macrophages, contribute to a milieu that promotes mutagenesis as well as the survival of mutated mesothelial cells. […] In mesothelioma, the surrounding stroma is not merely a scaffold but promotes tumor growth, invasion and protection from an anti-tumor immune response. Many genes related to the synthesis of, and interaction with, extracellular matrix (ECM) are upregulated in RNA expression analyses of mesothelioma specimens. These ECM-related genes are more associated with biphasic, desmoplastic and sarcomatoid variants—the histological subtypes with poorer prognoses. […] Furthermore, the stroma and stromal cells provide a scaffold for invasion, a barrier to the immune response and stimulate tumor growth and the differentiation of immunosuppressive cells. […] While checkpoint inhibition represents an exciting development in the treatment of several solid tumors, the outcomes in mesothelioma have been less positive and may well be affected by the complex structure of the tumor microenvironment in mesothelioma.

• #2 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  A crucial role in this process is recognized to the pleural macrophages recruited at the inflammatory site, which, failing the attempts to eliminate the fibers, are subject to frustrated phagocytosis, a process leading to activation of Nicotinamide adenine dinucleotide phosphate (NADPH), the generation of reactive oxygen species (ROS) and release of proinflammatory molecules (IL-1β, IL-8, IL-6 and TNF-α). […] Accumulation of asbestos fibers leads to aberrant activation of intracellular pathways and transcriptional processes responsible for the malignant transformation of mesothelial cells and the development of a unique inflammatory microenvironment. […] Indeed, tumor-associated macrophages (TAMs), T regulatory cells (Treg), such as cancer-associated fibroblasts (CAFs), are the most abundant population of MPM infiltration, that, in response to pro-tumoral signals, acquire malignant and immunosuppressive properties, influencing the progression of the tumor.

• #2 The pathogenesis of mesothelioma is driven by a dysregulated translatome | Nature Communications

  https://www.nature.com/articles/s41467-021-25173-7

  Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. […] The mechanisms of carcinogenesis driven by asbestos exposure are poorly understood and our limited knowledge of the molecular changes associated with MpM severely hampers therapeutic development. […] In addition to mutations and deletions in DNA that initiate tumorigenesis, it is well accepted that dysregulated cytoplasmic control of gene expression at the level of mRNA translation has a major role in both cancer development and progression. […] Dysregulation of eIF4F complex members drives tumorigenesis via increased synthesis of proteins that are normally poorly translated, particularly those encoding growth factors and oncogenes. […] Here, we show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis, and this results in an enhanced global rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and reprogramming of metabolic outputs.

• #2 The pathogenesis of mesothelioma is driven by a dysregulated translatome

  https://eprints.gla.ac.uk/248582/

  Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. […] The disease primarily results from loss of tumour suppressor gene function and there are no druggable driver oncogenes associated with MpM. […] We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. […] This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. […] These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. […] Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. […] Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.

• #2 Causes and Pathogenesis of Malignant Mesothelioma | IntechOpen

  https://www.intechopen.com/chapters/80836

  Recently, many researchers are concerned with the role of BAP1 in mesothelioma. […] The identification of BAP1 as a key regulator of cell death and metabolism aided in the description of the complex set of molecular events mediated by asbestos carcinogenesis. […] Taking into consideration the functional role of BAP1 in many cellular pathways implicated in cancer, it is not surprising that the BAP1 gene is mutated in a variety of tumors. […] More research is needed to provide a full picture of the genes that predispose to mesothelioma and their role in the molecular pathways of asbestos carcinogenesis that have been revealed, such as chronic inflammation and altered metabolism. […] Carbon nanotubes are one-dimensional fibrous nanomaterials that resemble asbestos fibers in their physical properties. […] Long, thin, biopersistent fibers are thought to enter the pleural space, obstruct clearance through lymphatic stomata on the parietal pleura, and cause frustrated phagocytosis, oxidant generation, and persistent inflammation, ultimately leading to MM.

• #2 The pathogenesis of mesothelioma – PubMed

  https://pubmed.ncbi.nlm.nih.gov/11836664/

  Asbestos appears to increase SV40-mediated transformation of human mesothelial cells in vitro, suggesting that asbestos and SV40 may be cocarcinogens. […] Mesothelioma appears to have a complex etiology in which environmental carcinogens (asbestos and erionite), ionizing radiation, viruses, and genetic factors act alone or in concert to cause malignancy.

• #2 Mesothelioma – Conditions – Thoracic Group, New Jersey

  https://thoracicgroup.com/conditions/mesothelioma/

  The only known carcinogen implicated in the pathogenesis of pleural mesothelioma is asbestos exposure, which is identified in at least 80 percent of cases. […] Because not everyone exposed to asbestos develops mesothelioma, there is growing interest in finding genetic mutations responsible for disease susceptibility. Mutations in the BAP1 tumor suppressor gene have been reported, among others. […] In the lung, macrophages (a type of white blood cell) attempt to ingest and destroy the remaining fibers. However, the indestructible nature of these fibers resists degradation. Eventually, some fibers pass through the lung and into the pleural space, where the asbestos fibers come in contact with the pleura. In the process, chemical substances are released that cause a slow inflammatory and mutagenic response, as there is an uncontrolled production of macrophages and mutation of the mesothelial cells.

• #2 Mesothelioma Pathogenesis

  http://www.mesothelioma-mesothelioma.com/pathogenesis.htm

  The pathogenesis of mesothelioma in humans is predicated on the transport of asbestos fibers to the pleura of the lungs the fluid-filled sac that surrounds the lungs. These fibers induce an immune system response, by macrophages and other specialized cells, to the lesions that occur as a result of asbestos-fiber irritation of tissues. These lesions continue to attract, and aggregate, specialized cells, causing cellular changes within the lesion that terminate in a malignant tumor. […] Evidence gathered from animal experiments indicates that asbestos acts as a complete carcinogen, though the molecular mechanisms of malignancy are not entirely clear. However, research indicates that asbestos fibers act directly on chromosomes, or structural proteins within the cell wall, to effect complex changes, with chromosome 22 showing the most distinct changes. These changes can lead to either deletion of tumor suppressing genes or the prevention of apoptosis (programmed cell death) or activation of oncogenes, via the interposition of foreign DNA, which asbestos appears to facilitate.

• #2 SciELO Brazil – Malignant pleural mesothelioma: an update Malignant pleural mesothelioma: an update

  https://www.scielo.br/j/jbpneu/a/f6Vk7bFyzjZTStkn9r5s4HD/?lang=en

  Although the association between asbestos exposure and mesothelioma pathogenesis is widely accepted, a common hypothesis has not been reached to explain it. Up to 80% of MPM patients have been previously exposed to asbestos. However, the reason for only a small proportion of asbestos-exposed individuals develop MM (2-10%) remains unknown. […] Molecular mechanisms associated with MM pathogenesis. Inhaled asbestos fibers transverse terminal airways and lodge themselves in the pleural space. Macrophages try to phagocytize these fibers without effect and in doing that they release reactive oxygen species and reactive nitrogen species, which may promote genotoxic damage, and recruit other inflammatory and immune cells. Repeated DNA damage by ROS and RNS may lead to the accumulation of oncogenic mutations in the mesothelial cells. The genes most frequently mutated in mesothelioma and that may be associated with malignant transformation of mesothelial cells are involved with DNA repair, the Hippo pathway, cell cycle control, DNA methylation and the mTOR pathway. Germ line mutations in genes associated with DNA repair (BAP1, BRCA1, CHECK2, etc) are found in 12% of mesothelioma patients and are associated with earlier disease onset and good prognosis. In parallel, the inflammatory mediators released in the microenvironment may promote cell survival (inhibiting apoptotic signals) and stimulate mesothelial cell proliferation (even in the presence of DNA damage), activate fibroblast to produce extracellular matrix proteins, and promote neoangiogenesis. These modifications favor tumor growth and create an immunosuppressive milieu.

• #2 Malignant pleural mesothelioma: new mechanism of spread discovered

  https://www.meduniwien.ac.at/web/en/about-us/news/detailsite/2018/news-im-dezember-2018/malignant-pleural-mesothelioma-new-mechanism-of-spread-discovered/

  If FGF2 and EGF are in play, the tumour subtype becomes more aggressive. […] In a further step, the researchers showed that tumour cells lost their aggressive characteristics again as soon as they encountered substances that blockade the effect of FGF2 and EGF. […] Blockading these signals could therefore offer new approaches for treating certain aggressive forms of mesothelioma.

• #3 Mesothelioma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Mesothelioma_pathophysiology

  Asbestos causes DNA damage directly by mechanically interfering with the segregation of chromosomes during mitosis and indirectly by inducing mesothelial cells and macrophages, to release mutagenic reactive oxygen and nitrogen species. Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma. […] Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.

• #3 How asbestos and other fibers cause mesothelioma – Gaudino – Translational Lung Cancer Research

  https://tlcr.amegroups.org/article/view/36019/html

  Chronic inflammation plays a major role in the pathogenesis and tumorigenesis induced by asbestos and other carcinogenic mineral fibers. […] The role of HMGB1 and related chronic inflammation is supported by the report on the preventative role of aspirin for mesothelioma, targeting HMGB1 activities and inflammation, and on the antitumor activity of aspirin in mesothelioma xenograft models. […] The current approach adopted in the field of carcinogens is to combine genetics and environmental studies to study GxE interactions. […] The mechanisms of cellular transformation following the exposure of HM to carcinogenic mineral fibers was elucidated by the discovery of the role of chronic inflammation mediated by HMGB1 and the inflammasome. Moreover, the identification of BAP1 as a main controller of cell death and metabolism contributed to the definition of the complex array of molecular events mediated by asbestos carcinogenesis.

• #3 Mesothelioma: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/280367-overview

  Interleukin-8 has direct growth-potentiating activity in mesothelial cell lines. Malignant mesothelioma has also been linked to therapeutic radiation using thorium dioxide and zeolite, a silicate in the soil. […] An etiologic role for simian virus 40 in malignant mesothelioma has been suggested. However, although asbestos exposure alone has been associated with malignant mesothelioma, simian virus 40 alone has not. Thus, some epidemiologic evidence exists that simian virus 40 is a possible cocarcinogen. Its direct role at this point is still controversial. […] Most malignant mesotheliomas have complex karyotypes, with extensive aneuploidy and the rearrangement of many chromosomes. […] Loss of 1 copy of chromosome 22 is the single most common karyotypic change in malignant mesothelioma. Other chromosomal changes commonly observed include deletions in the chromosome arms 1p, 3p, 9p, and 6q. Several changes in the tumor suppressor genes p16 (CDKN2A) and p14 (ARF) and loss of function of neurofibromin-2 (NF2) have also been noted.

• #3 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  A crucial role in this process is recognized to the pleural macrophages recruited at the inflammatory site, which, failing the attempts to eliminate the fibers, are subject to frustrated phagocytosis, a process leading to activation of Nicotinamide adenine dinucleotide phosphate (NADPH), the generation of reactive oxygen species (ROS) and release of proinflammatory molecules (IL-1β, IL-8, IL-6 and TNF-α). […] Accumulation of asbestos fibers leads to aberrant activation of intracellular pathways and transcriptional processes responsible for the malignant transformation of mesothelial cells and the development of a unique inflammatory microenvironment. […] Indeed, tumor-associated macrophages (TAMs), T regulatory cells (Treg), such as cancer-associated fibroblasts (CAFs), are the most abundant population of MPM infiltration, that, in response to pro-tumoral signals, acquire malignant and immunosuppressive properties, influencing the progression of the tumor.

• #3 Malignant pleural mesothelioma: an epidemiological perspective – Robinson- Annals of Cardiothoracic Surgery

  https://www.annalscts.com/article/view/1053/1582

  Malignant mesothelioma is a tumour arising from the mesothelial lining of the pleura, peritoneum, pericardium and tunica vaginalis. […] The association of mesothelioma with asbestos exposure is well established, with an aetiological fraction above 80%. […] The DNA virus, Simian virus 40 (SV40), has been associated with malignant mesothelioma and has been suggested as a causal co-factor. […] The latency of mesothelioma, that is the time elapsed between first exposure to asbestos and the diagnosis of disease, is long. […] Although short or low-level asbestos exposures have been linked to the development of mesothelioma, the risk of disease demonstrates dose dependence. […] The evidence has been deemed sufficient by the World Health Organisation (WHO) to conclude that all types of asbestos cause cancer in humans.

• #4 Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

  https://www.mdpi.com/2072-6694/13/22/5664

  MPM is characterized by a low tumor mutation burden (TMB), uncommon genetic aberrations, and recurrent somatic mutations in tumor suppressor genes, in both asbestos and non-asbestos induced tumors. […] The deletion of this gene affected the cell cycle regulating function of pRB and p53. […] For its proximity to CDKN2A, the methylthioadenosine phosphorylase (MTAP) gene is frequently co-deleted in different cancer types, including malignant mesothelioma. […] Other common mutations in mesothelioma are in chromosome 3, involving the loss of the BAP1 gene, in chromosome 22 enclosing the neurofibromin2 (NF2) gene, and in TP53. […] BAP-1 loss, together with MTAP/CDKN2A deletion, has been recently proposed as useful markers to improve the diagnostic sensitivity for MPM. […] Different from other cancers, driver mutations have not been found in mesothelioma and the pathogenesis of this cancer is undoubtedly related principally to the inflammatory microenvironment created by asbestos deposition in the pleura that stimulates the immune response.

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