Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma
- 31 January 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (3), 598-604
- https://doi.org/10.1158/1078-0432.ccr-11-2259
Abstract
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. p16INK4a and p14ARF 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. Clin Cancer Res; 18(3); 598–604. ©2011 AACR.Keywords
This publication has 61 references indexed in Scilit:
- Germline BAP1 mutations predispose to malignant mesotheliomaNature Genetics, 2011
- Germline mutations in BAP1 predispose to melanocytic tumorsNature Genetics, 2011
- Malignant mesothelioma: Facts, Myths, and HypothesesJournal of Cellular Physiology, 2011
- Onconase mediated NFKβ downregulation in malignant pleural mesotheliomaOncogene, 2011
- Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsThe Lancet, 2011
- Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammationProceedings of the National Academy of Sciences of the United States of America, 2010
- Activated TNF-α/NF-κB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout miceProceedings of the National Academy of Sciences of the United States of America, 2009
- The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesisNature Immunology, 2009
- The Nalp3 inflammasome is essential for the development of silicosisProceedings of the National Academy of Sciences of the United States of America, 2008
- TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesisProceedings of the National Academy of Sciences of the United States of America, 2006