International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Special Issue on Mechanisms of Mesothelioma Heterogeneity: Highlights and Open Questions

by Emanuela Felley-Bosco

Int. J. Mol. Sci. 2018, 19(11), 3560; https://doi.org/10.3390/ijms19113560 - 12 Nov 2018

Cited by 5 | Viewed by 2568

Abstract

This editorial aims to synthesize the eleven papers that have contributed to this special issue, where the mechanisms of mesothelioma heterogeneity have been tackled from different angles. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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Research

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16 pages, 2667 KiB

Open AccessCommunication

Genomic Deletion of BAP1 and CDKN2A Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures

by Kadir Harun Sarun, Kenneth Lee, Marissa Williams, Casey Maree Wright, Candice Julie Clarke, Ngan Ching Cheng, Ken Takahashi and Yuen Yee Cheng

Int. J. Mol. Sci. 2018, 19(10), 3056; https://doi.org/10.3390/ijms19103056 - 7 Oct 2018

Cited by 5 | Viewed by 4472

Abstract

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other [...] Read more.

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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17 pages, 5703 KiB

Open AccessArticle

Experimental Model of Human Malignant Mesothelioma in Athymic Mice

by Didier J. Colin, David Cottet-Dumoulin, Anna Faivre, Stéphane Germain, Frédéric Triponez and Véronique Serre-Beinier

Int. J. Mol. Sci. 2018, 19(7), 1881; https://doi.org/10.3390/ijms19071881 - 26 Jun 2018

Cited by 15 | Viewed by 4493

Abstract

Malignant pleural mesothelioma (MPM) is a thoracic aggressive cancer caused by asbestos exposure, which is difficult to diagnose and treat. Here, we characterized an in vivo orthotopic xenograft model consisting of human mesothelioma cells (designed as H2052/484) derived from a pleural NCI-H2052 tumor [...] Read more.

Malignant pleural mesothelioma (MPM) is a thoracic aggressive cancer caused by asbestos exposure, which is difficult to diagnose and treat. Here, we characterized an in vivo orthotopic xenograft model consisting of human mesothelioma cells (designed as H2052/484) derived from a pleural NCI-H2052 tumor injected in partially immunodeficient athymic mice. We assessed tumor formation and tumor-dependent patterns of inflammation. H2052/484 cells conserved their mesothelioma phenotype and most characteristics from the parental NCI-H2052 cells. After intra-thoracic injection of H2052/484 cells, thoracic tumors developed in nearly all mice (86%) within 14 days, faster than from parental NCI-H2052 cells. When the mice were euthanized, the pleural lavage fluid was examined for immune cell profiles. The pleural immune cell population increased with tumor development. Interestingly, the proportion of myeloid-derived suppressor cell and macrophage (especially CD206⁺ M2 macrophages) populations increased in the pleural fluid of mice with large mesothelioma development, as previously observed in immunocompetent mice. This reliable orthotopic model recapitulates human mesothelioma and may be used for the study of new treatment strategies. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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11 pages, 1587 KiB

Open AccessCommunication

Non-Coding Transcript Heterogeneity in Mesothelioma: Insights from Asbestos-Exposed Mice

by Emanuela Felley-Bosco and Hubert Rehrauer

Int. J. Mol. Sci. 2018, 19(4), 1163; https://doi.org/10.3390/ijms19041163 - 11 Apr 2018

Cited by 7 | Viewed by 4128

Abstract

Mesothelioma is an aggressive, rapidly fatal cancer and a better understanding of its molecular heterogeneity may help with making more efficient therapeutic strategies. Non-coding RNAs represent a larger part of the transcriptome but their contribution to diseases is not fully understood yet. We [...] Read more.

Mesothelioma is an aggressive, rapidly fatal cancer and a better understanding of its molecular heterogeneity may help with making more efficient therapeutic strategies. Non-coding RNAs represent a larger part of the transcriptome but their contribution to diseases is not fully understood yet. We used recently obtained RNA-seq data from asbestos-exposed mice and performed data mining of publicly available datasets in order to evaluate how non-coding RNA contribute to mesothelioma heterogeneity. Nine non-coding RNAs are specifically elevated in mesothelioma tumors and contribute to human mesothelioma heterogeneity. Because some of them have known oncogenic properties, this study supports the concept of non-coding RNAs as cancer progenitor genes. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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Review

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15 pages, 261 KiB

Open AccessReview

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

by Didier Jean and Marie-Claude Jaurand

Int. J. Mol. Sci. 2018, 19(8), 2191; https://doi.org/10.3390/ijms19082191 - 27 Jul 2018

Cited by 11 | Viewed by 3476

Abstract

Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. [...] Read more.

Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by Cdkn2a and Trp53 seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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14 pages, 782 KiB

Open AccessReview

Heterogeneity in Malignant Pleural Mesothelioma

by Kathrin Oehl, Bart Vrugt, Isabelle Opitz and Mayura Meerang

Int. J. Mol. Sci. 2018, 19(6), 1603; https://doi.org/10.3390/ijms19061603 - 30 May 2018

Cited by 40 | Viewed by 5246

Abstract

Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses [...] Read more.

Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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28 pages, 13412 KiB

Open AccessReview

In Silico and In Vitro Analyses of LncRNAs as Potential Regulators in the Transition from the Epithelioid to Sarcomatoid Histotype of Malignant Pleural Mesothelioma (MPM)

by Anand S. Singh, Richard Heery and Steven G. Gray

Int. J. Mol. Sci. 2018, 19(5), 1297; https://doi.org/10.3390/ijms19051297 - 26 Apr 2018

Cited by 17 | Viewed by 4390

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. At present, treatment options are limited, with no second line chemotherapy for those who fail first line therapy. Extensive efforts are ongoing in a bid to characterise the underlying molecular [...] Read more.

Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. At present, treatment options are limited, with no second line chemotherapy for those who fail first line therapy. Extensive efforts are ongoing in a bid to characterise the underlying molecular mechanisms of mesothelioma. Recent research has determined that between 70–90% of our genome is transcribed. As only 2% of our genome is protein coding, the roles of the remaining proportion of non-coding RNA in biological processes has many applications, including roles in carcinogenesis and epithelial–mesenchymal transition (EMT), a process thought to play important roles in MPM pathogenesis. Non-coding RNAs can be separated loosely into two subtypes, short non-coding RNAs (<200 nucleotides) or long (>200 nucleotides). A significant body of evidence has emerged for the roles of short non-coding RNAs in MPM. Less is known about the roles of long non-coding RNAs (lncRNAs) in this disease setting. LncRNAs have been shown to play diverse roles in EMT, and it has been suggested that EMT may play a role in the aggressiveness of MPM histological subsets. In this report, using both in vitro analyses on mesothelioma patient material and in silico analyses of existing RNA datasets, we posit that various lncRNAs may play important roles in EMT within MPM, and we review the current literature regarding these lncRNAs with respect to both EMT and MPM. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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12 pages, 279 KiB

Open AccessReview

Heterogeneity in Immune Cell Content in Malignant Pleural Mesothelioma

by Jorien Minnema-Luiting, Heleen Vroman, Joachim Aerts and Robin Cornelissen

Int. J. Mol. Sci. 2018, 19(4), 1041; https://doi.org/10.3390/ijms19041041 - 30 Mar 2018

Cited by 57 | Viewed by 5326

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited therapy options and dismal prognosis. In recent years, the role of immune cells within the tumor microenvironment (TME) has become a major area of interest. In this review, we discuss the current [...] Read more.

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited therapy options and dismal prognosis. In recent years, the role of immune cells within the tumor microenvironment (TME) has become a major area of interest. In this review, we discuss the current knowledge of heterogeneity in immune cell content and checkpoint expression in MPM in relation to prognosis and prediction of treatment efficacy. Generally, immune-suppressive cells such as M2 macrophages, myeloid-derived suppressor cells and regulatory T cells are present within the TME, with extensive heterogeneity in cell numbers. Infiltration of effector cells such as cytotoxic T cells, natural killer cells and T helper cells is commonly found, also with substantial patient to patient heterogeneity. PD-L1 expression also varied greatly (16–65%). The infiltration of immune cells in tumor and associated stroma holds key prognostic and predictive implications. As such, there is a strong rationale for thoroughly mapping the TME to better target therapy in mesothelioma. Researchers should be aware of the extensive possibilities that exist for a tumor to evade the cytotoxic killing from the immune system. Therefore, no “one size fits all” treatment is likely to be found and focus should lie on the heterogeneity of the tumors and TME. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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18 pages, 7896 KiB

Open AccessReview

NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma

by Tatsuhiro Sato and Yoshitaka Sekido

Int. J. Mol. Sci. 2018, 19(4), 988; https://doi.org/10.3390/ijms19040988 - 26 Mar 2018

Cited by 78 | Viewed by 11489

Abstract

The neurofibromatosis type 2 (NF2) gene encodes merlin, a tumor suppressor protein frequently inactivated in schwannoma, meningioma, and malignant mesothelioma (MM). The sequence of merlin is similar to that of ezrin/radixin/moesin (ERM) proteins which crosslink actin with the plasma membrane, suggesting [...] Read more.

The neurofibromatosis type 2 (NF2) gene encodes merlin, a tumor suppressor protein frequently inactivated in schwannoma, meningioma, and malignant mesothelioma (MM). The sequence of merlin is similar to that of ezrin/radixin/moesin (ERM) proteins which crosslink actin with the plasma membrane, suggesting that merlin plays a role in transducing extracellular signals to the actin cytoskeleton. Merlin adopts a distinct closed conformation defined by specific intramolecular interactions and regulates diverse cellular events such as transcription, translation, ubiquitination, and miRNA biosynthesis, many of which are mediated through Hippo and mTOR signaling, which are known to be closely involved in cancer development. MM is a very aggressive tumor associated with asbestos exposure, and genetic alterations in NF2 that abrogate merlin’s functional activity are found in about 40% of MMs, indicating the importance of NF2 inactivation in MM development and progression. In this review, we summarize the current knowledge of molecular events triggered by NF2/merlin inactivation, which lead to the development of mesothelioma and other cancers, and discuss potential therapeutic targets in merlin-deficient mesotheliomas. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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27 pages, 1035 KiB

Open AccessReview

Secreted and Tissue miRNAs as Diagnosis Biomarkers of Malignant Pleural Mesothelioma

by Vanessa Martínez-Rivera, María Cristina Negrete-García, Federico Ávila-Moreno and Blanca Ortiz-Quintero

Int. J. Mol. Sci. 2018, 19(2), 595; https://doi.org/10.3390/ijms19020595 - 17 Feb 2018

Cited by 25 | Viewed by 5181

Abstract

Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates in the pleura, is diagnosed in advanced stages and has a poor prognosis. Accurate diagnosis of MPM is often difficult and complex, and the gold standard diagnosis test is based on [...] Read more.

Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates in the pleura, is diagnosed in advanced stages and has a poor prognosis. Accurate diagnosis of MPM is often difficult and complex, and the gold standard diagnosis test is based on qualitative analysis of markers in pleural tissue by immunohistochemical staining. Therefore, it is necessary to develop quantitative and non-subjective alternative diagnostic tools. MicroRNAs are non-coding RNAs that regulate essential cellular mechanisms at the post-transcriptional level. Recent evidence indicates that miRNA expression in tissue and body fluids is aberrant in various tumors, revealing miRNAs as promising diagnostic biomarkers. This review summarizes evidence regarding secreted and tissue miRNAs as biomarkers of MPM and the biological characteristics associated with their potential diagnostic value. In addition to studies regarding miRNAs with potential diagnostic value for MPM, studies that aimed to identify the miRNAs involved in molecular mechanisms associated with MPM development are described with an emphasis on relevant aspects of the experimental designs that may influence the accuracy, consistency and real diagnostic value of currently reported data. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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23 pages, 635 KiB

Open AccessReview

Heterogeneous Contributing Factors in MPM Disease Development and Progression: Biological Advances and Clinical Implications

by Bhairavi Tolani, Luis A. Acevedo, Ngoc T. Hoang and Biao He

Int. J. Mol. Sci. 2018, 19(1), 238; https://doi.org/10.3390/ijms19010238 - 13 Jan 2018

Cited by 17 | Viewed by 5312

Abstract

Malignant pleural mesothelioma (MPM) tumors are remarkably aggressive and most patients only survive for 5–12 months; irrespective of stage; after primary symptoms appear. Compounding matters is that MPM remains unresponsive to conventional standards of care; including radiation and chemotherapy. Currently; instead of relying [...] Read more.

Malignant pleural mesothelioma (MPM) tumors are remarkably aggressive and most patients only survive for 5–12 months; irrespective of stage; after primary symptoms appear. Compounding matters is that MPM remains unresponsive to conventional standards of care; including radiation and chemotherapy. Currently; instead of relying on molecular signatures and histological typing; MPM treatment options are guided by clinical stage and patient characteristics because the mechanism of carcinogenesis has not been fully elucidated; although about 80% of cases can be linked to asbestos exposure. Several molecular pathways have been implicated in the MPM tumor microenvironment; such as angiogenesis; apoptosis; cell-cycle regulation and several growth factor-related pathways predicted to be amenable to therapeutic intervention. Furthermore, the availability of genomic data has improved our understanding of the pathobiology of MPM. The MPM genomic landscape is dominated by inactivating mutations in several tumor suppressor genes; such as CDKN2A; BAP1 and NF2. Given the complex heterogeneity of the tumor microenvironment in MPM; a better understanding of the interplay between stromal; endothelial and immune cells at the molecular level is required; to chaperone the development of improved personalized therapeutics. Many recent advances at the molecular level have been reported and several exciting new treatment options are under investigation. Here; we review the challenges and the most up-to-date biological advances in MPM pertaining to the molecular pathways implicated; progress at the genomic level; immunological progression of this fatal disease; and its link with developmental cell pathways; with an emphasis on prognostic and therapeutic treatment strategies. Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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912 KiB

Open AccessCase Report

Peritoneal Mesothelioma with Residential Asbestos Exposure. Report of a Case with Long Survival (Seventeen Years) Analyzed by Cgh-Array

by Gabriella Serio, Federica Pezzuto, Andrea Marzullo, Anna Scattone, Domenica Cavone, Alessandra Punzi, Francesco Fortarezza, Mattia Gentile, Antonia Lucia Buonadonna, Mattia Barbareschi and Luigi Vimercati

Int. J. Mol. Sci. 2017, 18(8), 1818; https://doi.org/10.3390/ijms18081818 - 22 Aug 2017

Cited by 27 | Viewed by 4775

Abstract

Malignant mesothelioma is a rare and aggressive tumor with limited therapeutic options. We report a case of a malignant peritoneal mesothelioma (MPM) epithelioid type, with environmental asbestos exposure, in a 36-year-old man, with a long survival (17 years). The patient received standard treatment [...] Read more.

Malignant mesothelioma is a rare and aggressive tumor with limited therapeutic options. We report a case of a malignant peritoneal mesothelioma (MPM) epithelioid type, with environmental asbestos exposure, in a 36-year-old man, with a long survival (17 years). The patient received standard treatment which included cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods and Results: Molecular analysis with comparative genomic hybridization (CGH)-array was performed on paraffin-embedded tumoral samples. Multiple chromosomal imbalances were detected. The gains were prevalent. Losses at 1q21, 2q11.1→q13, 8p23.1, 9p12→p11, 9q21.33→q33.1, 9q12→q21.33, and 17p12→p11.2 are observed. Chromosome band 3p21 (BAP1), 9p21 (CDKN2A) and 22q12 (NF2) are not affected. Conclusions: the defects observed in this case are uncommon in malignant peritoneal mesothelioma. Some chromosomal aberrations that appear to be random here, might actually be relevant events explaining the response to therapy, the long survival and, finally, may be considered useful prognostic factors in peritoneal malignant mesothelioma (PMM). Full article

(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)

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