Asbestos-Related Pleural Diseases: The Role of Gene-Environment Interactions

Several pleural diseases have been associated with asbestos exposure. Asbestos exposure may lead to the development of benign pleural diseases, such as pleural plaques, diffuse pleural thickening, and pleural effusion, as well as to the development of malignant mesothelioma, a highly aggressive tumour of the pleura. Asbestos exposure related to pleural diseases may be occupational or environmental. Although the causal relationship between asbestos-related pleural diseases and asbestos exposure has been well confirmed, the role of genetic factors in the development of these diseases needs to be further investigated and elucidated. The results of the studies performed so far indicate that in addition to asbestos exposure, genetic factors as well as the interactions between genetic factors and asbestos exposure may have an important impact on the risk of asbestos-related pleural diseases, especially malignant mesothelioma. This chapter aims to present how the risk of developing asbestos-related pleural diseases may be influenced by asbestos exposure, genetic factors, interactions between different genetic factors, as well as interactions between different genetic factors and asbestos exposure

Occupational exposures and genetic susceptibility to lung cancer and pleural mesothelioma: a systematic review

Background The risk of occupationally related lung cancer, as well as pleural mesothelioma, in association with genetic polymorphisms, has been investigated with contradictory results. This systematic review aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and lung cancer and pleural mesothelioma. Methods We searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. Studies were considered eligible if they had assessed the association between occupational exposures and lung cancer/pleural mesothelioma in relation to genetic polymorphisms. Results Sixteen studies were included, of which eleven on lung cancer and six on mesothelioma, of which one was in common. NAT2 slow acetylator genotype confers an increased risk of pleural mesothelioma in subjects exposed to asbestos (OR=2.10; 95% CI=1.10-4.10), especially in combination with the GSTM1 null genotype (OR=3.60; 95% CI=1.30-9.60). GSTT1 null and CYP1A1 Msp1 T6235C (T/C+C/C) genotype carriers exposed to arsenic, uranium, asbestos and other chemical agents have an increased risk of lung cancer respect to not exposed wild type genotypes (OR=1.33; 95% CI=0.67-2.64, OR=2.20; 95% CI=1.11-4.35, respectively). Conclusion Genetic polymorphisms might modulate individual susceptibility to lung cancer and pleural mesothelioma in occupationally exposed subjects

Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma:A Comprehensive Review

Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos–gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies

Biomarkers in the prevention and follow-up of workers exposed to asbestos

Although in most developed countries the use of asbestos is banned, there is still a consistent portion of the world where asbestos extraction, trading and manufacturing of asbestos-made products is largely diffuse. Worldwide, hundreds of millions of people are at risk of developing an asbestos caused disease because of occupational, environmental or domestic exposure. The WHO estimates that asbestos is responsible for more than 100,000 deaths yearly. This scenario has prompted the research on biomarkers potentially useful for early diagnosis, prognosis and preventive programs on exposed population as well. Here we reviewed the up-to-date literature on this field of research highlighting that along with mesothelin and osteopontin (OPN), some more recently investigated molecules, such as high mobility group box 1 (HMGB1) protein, fibulin-3 and some miRNAs showed very promising. Most of the carried-out studies showed an interesting diagnostic and prognostic performance of some biomarkers, but since they usually lack adequate either specificity or sensitivity, their use in screening or in preventive programs is still not recommended on a routine basis. However, this review suggests the need for more reliable experimental design involving larger population and preferring longitudinal screening of asbestos exposed individuals rather than a single baseline assessment investigation. In addition, given their better diagnostic accuracy, the use of panels including several biomarkers is highly recommended

Factors that Impact Susceptibility to Fiber-Induced Health Effects

Asbestos and related fibers are associated with a number of adverse health effects, including malignant mesothelioma (MM), an aggressive cancer that generally develops in the surface serosal cells of the pleural, pericardial, and peritoneal cavities. Although approximately 80% of individuals with MM are exposed to asbestos, fewer than 5% of asbestos workers develop MM. In addition to asbestos, other mineralogical, environmental, genetic, and possibly viral factors might contribute to MM susceptibility. Given this complex etiology of MM, understanding susceptibility to MM needs to be a priority for investigators in order to reduce exposure of those most at risk to known environmental carcinogens. In this review, the current body of literature related to fiber-associated disease susceptibility including age, sex, nutrition, genetics, asbestos, and other mineral exposure is addressed with a focus on MM, and critical areas for further study are recommended

Genome-Wide Profile of Pleural Mesothelioma versus Parietal and Visceral Pleura: The Emerging Gene Portrait of the Mesothelioma Phenotype

Malignant pleural mesothelioma is considered an almost incurable tumour with increasing incidence worldwide. It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura. Chromosomal and genomic aberrations of mesothelioma are diverse and heterogenous. Genome-wide profiling of mesothelioma versus parietal and visceral normal pleural tissue could thus reveal novel genes and pathways explaining its aggressive phenotype.Well-characterised tissue from five mesothelioma patients and normal parietal and visceral pleural samples from six non-cancer patients were profiled by Affymetrix oligoarray of 38 500 genes. The lists of differentially expressed genes tested for overrepresentation in KEGG PATHWAYS (Kyoto Encyclopedia of Genes and Genomes) and GO (gene ontology) terms revealed large differences of expression between visceral and parietal pleura, and both tissues differed from mesothelioma. Cell growth and intrinsic resistance in tumour versus parietal pleura was reflected in highly overexpressed cell cycle, mitosis, replication, DNA repair and anti-apoptosis genes. Several genes of the “salvage pathway” that recycle nucleobases were overexpressed, among them TYMS, encoding thymidylate synthase, the main target of the antifolate drug pemetrexed that is active in mesothelioma. Circadian rhythm genes were expressed in favour of tumour growth. The local invasive, non-metastatic phenotype of mesothelioma, could partly be due to overexpression of the known metastasis suppressors NME1 and NME2. Down-regulation of several tumour suppressor genes could contribute to mesothelioma progression. Genes involved in cell communication were down-regulated, indicating that mesothelioma may shield itself from the immune system. Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated. This could represent a genetical platform of the parietal pleura propensity to develop mesothelioma.Genome-wide microarray approach using complex human tissue samples revealed novel expression patterns, reflecting some important features of mesothelioma biology that should be further explored

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies

Exosomes And Their Role In Asbestos Exposure And Mesothelioma

Malignant mesothelioma (MM) is a locally invasive and highly aggressive cancer arising on the mesothelial surface of organ cavities (mainly pleural) as a direct result of asbestos exposure. The latency period of MM is long (20-50yrs) after initial asbestos exposure, and the prognostic outcomes are dismal with median life expectancy of 6-12 months post-diagnosis. There are no useful biomarkers for early MM diagnosis, no successful therapeutic interventions. These vast voids of knowledge led to our hypotheses that secreted vesicles, termed exosomes, play an important role in MM development and tumorigenic properties. Exosomes are nano-sized particles secreted from all cell types and carry biologically active cargo in the form of proteins, RNA, and lipids that can potently act as intercellular messengers in both healthy settings and disease states. We are the first to have conducted studies implicating the roles of exosomes in MM pathogenesis. Firstly, we analyzed the proteomic signature of exosomes from asbestos exposure models, in vitro and in vivo. Our in vitro data demonstrated that asbestos exposed lung epithelial cells and macrophages secrete exosomes with differentially abundant proteins compared to non-exposed controls and some of these proteins are relevant to asbestos exposure toxicology and MM development. Additionally, the exosomes from asbestos exposed cells significantly modulated the gene expression of target mesothelial cells in a way that reflected epithelial to mesenchymal transition and other tumorigenic properties. The in vivo mouse studies illustrated that mouse serum exosomes house differentially abundant proteins after asbestos exposure and this is measurable at an organism wide scale. Secondly, we assayed the miRNA composition of MM tumor exosomes compared to healthy mesothelial cell exosomes and found signature differences in miRNA abundances, particularly that MM tumor cells had significantly higher amounts of tumor suppressor miRNA, particularly miR-16-5p, in their exosomes. This led to the hypothesis that MM tumor cells preferentially secrete tumor suppressor miRNAs via exosomes to rid themselves of the anti-tumor effects. We employed exosomes secretion inhibitors and exosome force-feeding to demonstrate that MM cells do in fact secrete miR-16-5p (along with other tumor suppressor miRNAs) through exosomes and that this property can be targeted as a potentially novel therapeutic advance. Furthermore, we identified a mechanism of miR-16-5p loading into exosomes by the RNA binding protein HuR, and this mechanism is interestingly regulated by miR-16-5p itself in a negative feedback loop. Our studies thus far provide intriguing evidence on the role of exosomes in asbestos exposure and MM biology. We demonstrated the potential for exosomes as protein biomarkers in asbestos exposure and conduits of tumorigenic information to mesothelial cells. In addition, we incriminate exosomes as vehicles of tumor suppressor removal from MM tumor cells and we can target this as a potential n MM therapy

The role of the tumor suppressor gene, NF2, in the development of malignant mesothelioma

The highly aggressive cancer, malignant mesothelioma, responds poorly to available treatment options. As most individuals diagnosed with these tumors succumb to the disease within about 2 years of diagnosis, it is imperative to develop a more thorough understanding of molecular mechanisms of the disease and thus design more suitable therapeutic options. Neurofibromatosis Type 2 (NF2) is one of the most commonly inactivated tumor suppressor genes in mesothelioma. The downstream signaling pathways that may be disrupted as a result of this inactivation are not entirely understood. Conversely, the tumor suppressor gene that is often referred to as the Genome Gatekeeper, TP53, is rarely inactivated in mesothelioma tumors. As TP53 is mutated in the majority of human cancers, in those cancers where TP53 is not mutated, its function may be regulated by other mechanisms. Evidence suggests that NF2 may be upstream in a signaling cascade of TP53, such that NF2 is responsible for MDM2 degradation. MDM2 is a negative regulator of p53 (the protein product of TP53), so that loss of NF2 would ultimately result in decreased function of p53. The hypothesis of this study is that inactivation of NF2 plays a critical role in cellular growth dysregulation through altering normal regulation of MDM2 and thus p53 levels. To test this hypothesis, the role of the NF2 gene in regulating p53 function and cellular growth in normal mesothelial cells and in a mesothelioma cell culture model were assessed. Normal function of NF2 was restored by transfection of a wild-type NF2 construct in a mesothelioma cell culture model. Additionally, NF2 expression was reduced in normal mesothelial cells by shRNA knockdown. In both in vitro models, alterations in NF2 expression resulted in significant changes in cell cycle mechanisms, including proliferative, apoptotic, and cell cycle arrest. These events were linked to aberrant p53 function. Finally, an in vivo mouse model was used to determine the role Nf2 in the development of pleural mesothelioma following asbestos exposure. A better understanding of the molecular mechanisms that are disrupted following NF2 inactivation will help with design of more effective therapeutic strategies