Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma

Abstract

Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and NF-kB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. PI3K, AKT and the downstream mTOR are involved in cell growth and survival and are often found to be activated in mesothelioma. p16INK4a and p14ARF are frequently inactivated in human mesothelioma, and approximately 50% of mesotheliomas contain 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 that have benefit from certain therapies. Recent studies have demonstrated the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma; HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1 that, in turn, may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of ROS. HMGB1 and Nalp3 induce pro-inflammatory responses and lead to the secretion of IL-1β and TNF-α, 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 individuals genetically predisposed, 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.

Mesothelioma: recent highlights

“…Asbestos causes primary HM necrosis that result in the passive release of HMGB1 into the extracellular space. This, together with the prolonged bio-persistence of asbestos fibers, initiates a vicious cycle of chronic cell death and inflammation that over a period of many years can lead to mesothelioma (17). Thus, HMGB1 functions as a 'master switch' by which the chronic inflammation that drives mesothelioma growth is initiated and maintained.…”

Malignant Pleura Mesothelioma: Clinical Perspectives

“…Moreover, MPM cells appear resistant to apoptosis mechanisms, thus providing a mechanism for the continuous growth of malignant transformed cells. According to another hypothesis, the suppression of the tumor suppressor genes may enhance the development of the malignancy [3,4,8,40,[42][43][44]. As far as the asbestos type is concerned, it is thought that the chrysolite fibers are quickly removed from the lung without being translocated in the pleural cavity and initiating an inflammatory reaction that may possibly lead to MPM.…”

The Role of Cyclooxygenase-2, Epidermal Growth Factor Receptor and Aromatase in Malignant Mesothelioma

“…The phosphoinositide 3-kinase (PI3K)/AKT pathway, plays a critical role for the cell cycle progression in human MM cells [ Altomare et al,2005). AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in MM (Carbone et al, 2012). It was reported previously that STAT1 and STAT3 are deregulated MM (Kothmaier et al, 2008).The JAK/STAT signalling pathway is the principal signalling mechanism for growth factors in mammals.…”