Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma. Clin Cancer Res.

University of Hawaii Cancer Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Clinical Cancer Research (Impact Factor: 8.72). 11/2011; 18(3):598-604. DOI: 10.1158/1078-0432.CCR-11-2259
Source: PubMed


Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-κB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human mesothelioma, and ∼50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1β and TNF-α secretion and NF-κB activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection.

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Available from: Haining Yang, Jun 08, 2015
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    • "The presence of a genetic susceptibility gene raises implications for genetic counseling and treatment of MM. The possibility was raised that genetic testing for BAP1 mutations could identify among exposed cohorts of genetically susceptible individuals those that have the highest risk of developing MM[70]. Individuals with more than one family member with a diagnosis of MM or uveal melanoma could potentially be screened for germline BAP1 mutations in order to identify MM risk and provide earlier diagnosis and treatment options. "
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    ABSTRACT: Malignant mesothelioma (MM) is a fatal cancer of the pleural and peritoneal cavities caused predominantly by exposure to asbestos. Cohort studies suggest a genetic component to MM susceptibility. BAP1 is a tumour suppressor gene located at 3p21 and is one of the most commonly somatically lost or mutated genes in MM, occurring in approximately 40–60 % of tumours. Germline mutations in BAP1 appear to increase susceptibility to asbestos-induced MM. However, the frequency of germline BAP1 mutation is rare, not being observed in over 300 sporadic MM cases. Germline BAP1 mutation is characteristic of a heritable cancer predisposing syndrome with affected individuals developing malignancies such as MM, uveal and cutaneous melanoma at relatively high frequency. Here, we review the current research into BAP1 mutations in MM.
    Full-text · Article · Jan 2016
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    • "Given the heterogeneous and complex genetic nature of MPM [9] [10], many molecular aberrations underlying its progression and affecting clinical response have to be identified , while several trials of new biological agents in combination with pemetrexed and platinum are currently ongoing ( Previous studies supported preclinical investigations on key kinases that act as central regulators of the neoplastic process and are amenable to pharmacological inhibition. "
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a lethal disease with scarce therapeutic options, and preclinical studies on new targeted-agents are warranted. Because previous studies reported high c-Met expression and alterations in the microtubules network in most MPM samples, we evaluated the activity of the tivantinib, which has been recently suggested to affect microtubule polymerization in addition to inhibiting c-Met. In four MPM cell lines tivantinib inhibited both c-Met activity and microtubule polymerization, resulting in inhibition of cell-growth with IC50s ranging between 0.3 µM (MSTO-211H) and 2.4 µM (H2052). Furthermore tivantinib synergistically enhanced the antiproliferative and pro-apoptotic activity of pemetrexed, as detected by sulforhodamine-B-assay and flow cytometry. The synergistic interaction was associated with reduction of thymidylate synthase expression and inhibition of migratory activity. In aggregate, these data show the ability of tivantinib to specifically target key pathways in MPM cells and synergistically interact with pemetrexed, supporting further studies on this therapeutic approach.
    Full-text · Article · Dec 2014 · Current Drug Targets
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    • "Much of the fibrous material, including winchite and richterite, did not fall into the definition above, despite containing long, thin “asbestiform” mineral fibers. Since then, another mineral fiber in the zeolite family called erionite has been shown to be highly carcinogenic and causing pulmonary diseases similar to those seen with asbestos [10–12]. In addition, over the last few decades the manufacture and use of nanomaterials called “nanotubes” and “nanowires” have dramatically increased, leading to health concerns due to similarities to asbestos [13, 14]. "
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    ABSTRACT: Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA), a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a) a lack of statistical power due to relatively small or diffuse exposure cohorts, (b) exposure misclassification, (c) latency of clinical disease, (d) mild or subclinical entities that remain undetected or masked by other pathologies, or (e) effects that are specific to certain fiber types, so that analyses on mixed exposures do not reach statistical significance. This review summarizes epidemiological, animal model, and in vitro data related to asbestos exposures and autoimmunity. These combined data help build toward a better understanding of the fiber-associated factors contributing to immune dysfunction that may raise the risk of autoimmunity and the possible contribution to asbestos-related pulmonary disease.
    Full-text · Article · Apr 2014
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