Malignant pleural mesothelioma: current concepts in treatment

Tsiouris, Athanasios; Walesby, R.K.

doi:10.1038/ncponc0839

Cited by 44 publications

(39 citation statements)

References 39 publications

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“…Thus, we propose a novel combination of markers that may be useful for early diagnosis of MM, whereby improving the outcome of the ensuing therapy with novel, promising drugs (17,30,31). The importance of our findings may be reconciled with the currently very grim prognosis for mesothelioma patients.…”

Section: Discussionmentioning

confidence: 72%

Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

Amati¹,

Tomasetti²,

Scartozzi

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Improved detection methods for diagnosis of asymptomatic malignant mesothelioma (MM) are essential for an early and reliable detection and treatment of this type of neoplastic disease. Thus, focus has been on finding tumor markers in the blood that can be used for noninvasive detection of MM. Ninety-four asbestosexposed subjects defined at high risk, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the clinical significance of 8-hydroxy-2 ¶-deoxyguanosine (8OHdG) in WBCs and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors [platelet-derived growth factor B, hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor B (VEGFB)], and matrix proteases [matrix metalloproteinase (MMP) 2, MMP9, tissue inhibitor of metalloproteinase (TIMP) 1, and TIMP2] for potential early detection of MM. The area under receiver operating characteristic (ROC) curves indicate that 8OHdG levels can discriminate asbestosexposed subjects from healthy controls but not from MM patients. Significant area under ROC curve values were found for SMRPs, discriminating asbestos-exposed subjects from MM patients but not from healthy controls. Except for platelet-derived growth factor B, the hepatocyte growth factor, basic fibroblast growth factor, and VEGFB can significantly differentiate high-risk individuals from healthy control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, and TIMP2. In addition to the diagnostic performance defined by the ROC analysis, the sensitivity and specificity results of markers with clinical significance were calculated at defined cutoffs. The combination of 8OHdG, VEGFB, and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

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Section: Discussionmentioning

confidence: 72%

Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

Amati¹,

Tomasetti²,

Scartozzi

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Approximately 10,000 to 15,000 patients worldwide are newly diagnosed with MPM annually, and the number of patients is projected to increase over the next two decades in Asia and the United States (1,2). Although the inhalation of asbestos is a well-known risk factor, the lack of clinical symptoms in the early stages of MPM as well as of useful diagnostic markers makes early diagnosis virtually impossible.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

et al. 2009

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Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073-82]

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“…Despite considerable advances in the general understanding of its etiology and pathogenesis, MM remains incurable with standard cancer therapy modalities (14,15). Furthermore, this tumor has been predicted to increase the social burden by raising health care costs and the costs paid by industry and government in the form of compensation.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

Kashiwakura

Ochiai

Watanabe³

et al. 2008

Cancer Research

118

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REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH 2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional downregulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed downregulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

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Malignant pleural mesothelioma: current concepts in treatment

Cited by 44 publications

References 39 publications

Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

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