Update on the molecular biology of malignant mesothelioma

Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, California 94143, USA.
Cancer (Impact Factor: 4.89). 04/2007; 109(8):1454-61. DOI: 10.1002/cncr.22552
Source: PubMed

ABSTRACT Malignant mesothelioma (MM) is a highly aggressive tumor with a very poor prognosis. The disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of the first symptoms. Novel, more effective therapeutic strategies are needed for this inexorably fatal disease. Improvement in our understanding of the molecular biology of MM has identified promising new candidates for targeted treatments. In this review the key molecular signaling pathways, including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Wnt, and the cell cycle control genes p53, pRb, and bcl-2 that appear to play an important role in the pathogenesis of MM are explored.

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    • "Biochemical analyses demonstrated aberrant growth signaling with enhanced angiogenesis in mesothelioma, which suggests that blocking these signal pathways is a therapeutic strategy. Mesothelioma often up-regulated expression of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and the corresponding receptors (VEGFR, EGFR) (Strizzi et al. 2001; Lee et al. 2007). Furthermore, an expression level of hepatocyte growth factor (HGF) and the receptor, c-Met, is also augmented in a majority of mesothelioma specimens (Jagadeeswaran et al. 2006; Lee et al. 2015). "
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    ABSTRACT: The hepatocyte growth factor (HGF)/c-Met signal pathway is up-regulated in human mesothelioma and suppression of the HGF/c-Met signaling with a competitive inhibitor, NK4 homologous to HGF in the structure, produced anti-tumor effects to mesothelioma in a preclinical study. Mesothelioma is highly resistant to a number of chemotherapeutic agents but distant metastasis to extra-thoracic organs is relatively infrequent until the late stage. We planned to conduct a clinical study of gene therapy with adenoviruses expressing the NK4 gene (Ad-NK4) to control the local tumor growth. The study is designed to inject Ad-NK4 into the intrapleural cavity with a dose escalation manner from 10(10) to 10(12) virus particles per patient and to examine safety and possible clinical benefits. The clinical investigation is a first-in-human trial to use the NK4 gene and to block the HGF/c-Met pathway with gene medicine. We conducted in vivo animal experiments to examine the safety level as one of the preclinical studies, and showed that Ad DNA administered in the pleural cavity was detected in many parenchymal organs. Biochemical and pathological analyses showed that liver damages were the major adverse effects with little toxicity to other organs. These studies firstly demonstrated biodistribution and transgene expression after an intrapleural injection of Ad vectors in an animal study, which contrasts with an intravenous injection showing relatively rapid clearance of Ad-NK4. The clinical study can also provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells. These data will be crucial to judge whether local production of NK4 molecules can be an anti-cancer strategy. UMIN clinical trials registry, Japan. Register ID: UMIN15771.
    SpringerPlus 07/2015; 4(1):358. DOI:10.1186/s40064-015-1123-3
    • "It appears that the risk of mesothelioma and the risk of subsequent mortality correlate with cumulative exposure to asbestos fibers and also the type of fiber. Asbestos has been implicated as the main carcinogen.[12] "
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    ABSTRACT: This report highlights that pleural and peritoneal mesothelioma can occur without direct asbestos exposure as was seen in our young patient. The patient had indirect exposure for as short as 3 months as a child, 15 years earlier, when she was residing with her miner father in the district of Jharia, Jharkhand, which is an asbestos-rich mining area in eastern India. The patient presented with chest pain and breathlessness. Chest X-ray showed opaque right hemithorax. Typical contrast- computed tomography (CECT) enhanced radiological features included nodular, soft-tissue attenuation and homogenously enhancing rind-like mass causing scalloping of the underlying lung and liver. Similar lesions were also found involving the pelvis. Diagnosis of malignant mesothelioma was confirmed on lung biopsy. Under-reporting of exposure is usual because it is unrecognized by both patients and investigators.
    Journal of Clinical Imaging Science 06/2014; 4(1):35. DOI:10.4103/2156-7514.135662
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    • "Mesothelioma has an unusual molecular lesion linked with loss of tumor suppressor functions. The majority of mesothelioma has a deletion in the INK4A/ARF locus which encodes the p14ARF and the p16INK4A genes, but possesses the wild-type p53 gene [4]. Deletion of p16INK4A increases cyclin-dependent kinase 4/6 activities, which subsequently induces pRb phosphorylation and cell cycle progression. "
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    ABSTRACT: Interferons (IFNs) have been tested for the therapeutic effects in various types of malignancy, but mechanisms of the anti-tumors effects and the differential biological activities among IFN members are dependent on respective cell types. In this study, we examined growth inhibitory activities of type I and III IFNs on 5 kinds of human mesothelioma cells bearing wild-type p53 gene, and showed that type I IFNs but not type III IFNs decreased the cell viabilities. Moreover, growth inhibitory activities and up-regulated expression levels of the major histocompatibility complexes class I antigens were greater with IFN-β than with IFN-α treatments. Cell cycle analyses demonstrated that type I IFNs increased S- and G2/M-phase populations, and subsequently sub-G1-phase fractions. The cell cycle changes were also greater with IFN-β than IFN-α treatments, and these data collectively showed that IFN-β had stronger biological activities than IFN-α in mesothelioma. Type I IFNs-treated cells increased p53 expression and the phosphorylation levels, and activated apoptotic pathways. A combinatory use of IFN-β and cisplatin or pemetrexed, both of which are the current first-line chemotherapeutic agents for mesothelioma, produced synergistic anti-tumor effects, which were also evidenced by increased sub-G1-phase fractions. These data demonstrated firstly to our knowledge that IFN-β produced synergistic anti-tumor effects with cisplatin or pemetrexed on mesothelioma through up-regulated p53 expression.
    PLoS ONE 08/2013; 8(8):e72709. DOI:10.1371/journal.pone.0072709 · 3.23 Impact Factor
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