ijms-logo

Journal Browser

Journal Browser

Mesothelioma Heterogeneity: Potential Mechanisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2018) | Viewed by 55592

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Laboratory of Molecular Oncology, LABE40, Division of Thoracic Surgery, Sternwartstrasse 14, 8091 Zurich, Switzerland
Interests: mesothelioma biology; mesothelioma translational research; mesothelioma pre-clinical models; inflammation-related cancer; RNA editing

Special Issue Information

Dear Colleagues,

Mesothelioma is a rare aggressive cancer developing from the mesothelium. Recent molecular analyses have defined four different types of mesothelioma on the basis of gene expression, and two molecularly-defined groups based on prognosis. This Special Issue explores potential mechanisms causing this heterogeneity.

Announced papers will include heterogeneity sources: learned from experimental animal models; from 3D spheroids, in the NF2/Hippo pathway signaling; tumor microenvironment. We are open to suggestions which will cover other aspects contributing to heterogeneity

Dr. Emanuela Felley-Bosco
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mesothelioma
  • mesothelium
  • chronic inflammation
  • carcinogenesis
  • tumor microenvironment
  • tumor suppressor genes
  • cell-of-origin
  • signaling pathways

Published Papers (12 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review, Other

5 pages, 430 KiB  
Editorial
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 2284
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)
Show Figures

Figure 1

Research

Jump to: Editorial, Review, Other

16 pages, 2667 KiB  
Communication
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 - 07 Oct 2018
Cited by 5 | Viewed by 3998
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)
Show Figures

Graphical abstract

17 pages, 5703 KiB  
Article
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 4037
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)
Show Figures

Graphical abstract

11 pages, 1587 KiB  
Communication
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 3775
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)
Show Figures

Graphical abstract

Review

Jump to: Editorial, Research, Other

15 pages, 261 KiB  
Review
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 3124
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)
Show Figures

Graphical abstract

14 pages, 782 KiB  
Review
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 33 | Viewed by 4616
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)
Show Figures

Figure 1

28 pages, 13412 KiB  
Review
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 4016
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)
Show Figures

Figure 1

12 pages, 279 KiB  
Review
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 51 | Viewed by 4853
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)
Show Figures

Graphical abstract

18 pages, 7896 KiB  
Review
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 68 | Viewed by 10444
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)
Show Figures

Graphical abstract

27 pages, 1035 KiB  
Review
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 24 | Viewed by 4724
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)
Show Figures

Graphical abstract

23 pages, 635 KiB  
Review
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 4725
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)
Show Figures

Graphical abstract

Other

912 KiB  
Case 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 26 | Viewed by 4344
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)
Show Figures

Figure 1

Back to TopTop