Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma.

University of Hawaii Cancer Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Clinical Cancer Research (Impact Factor: 8.19). 11/2011; 18(3):598-604. DOI: 10.1158/1078-0432.CCR-11-2259
Source: PubMed

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. 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.

  • American Mineralogist 01/2014; 99(1):8-15. · 2.06 Impact Factor
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    ABSTRACT: Background Renal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clinically aggressive behavior. We report a case of a married couple in whom RCC with rhabdoid features concurrently occurred. The rarity of this event suggests that environmental factors may contribute to the etiology of RCC with rhabdoid features.Case presentationA 76-year-old Japanese woman was diagnosed with a hypervascular mass in the right kidney and tumor thrombus extending into the right atrium by enhanced computed tomography (CT). She underwent radical nephrectomy and tumor thrombectomy following systemic therapy with the tyrosine kinase inhibitor sunitinib. The histological evaluation denoted clear cell RCC with rhabdoid features. The patient died of cancer 12 months postoperatively. A 76-year-old man, her husband, presented with gross hematuria 2 weeks after his wife had undergone surgery. He had a long history of asbestos exposure. An abdominal CT scan revealed a hypervascular mass in the right kidney and tumor thrombus extending into the inferior vena cava. He also underwent radical nephrectomy and tumor thrombectomy. The histological evaluation also showed clear cell RCC with rhabdoid features. Bone metastasis occurred 12 months postoperatively, but he died of an unrelated cause 18 months after surgery.Conclusion Concurrent occurrence of RCC with rhabdoid features may not to be coincidental. Although further studies are warranted, asbestos exposure may contribute to the etiology of clear cell RCC with rhabdoid features.
    BMC Research Notes 01/2015; 8(1):3.
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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.
    Current Drug Targets 12/2014; 15(14). · 3.60 Impact Factor


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