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Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma

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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 (31 July 2021) | Viewed by 27834

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Special Issue Editors

Prof. Dr. Eric Santoni-Rugiu

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Guest Editor

1. Departnent of Pathology, Diagnostic Center, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen E., Denmark
2. Biotech Research & Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N., Denmark
Interests: malignant pleural mesothelioma; molecular alterations; novel biomarkers; molecular subtypes; diagnosis; prognosticators and predictors

Prof. Dr. Jens Benn Sørensen

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Guest Editor

Department of Oncology, Center for Cancer and Organ Diseases, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen E., Denmark
Interests: malignant pleural mesothelioma; molecular alterations; novel biomarkers; prognosticators and predictors; targeted therapy; immunotherapy

Special Issue Information

Dear Colleagues,

Malignant pleural mesothelioma (MPM) is a very aggressive cancer originating from the mesothelial cells lining the pleural cavity, usually associated with exposure to asbestos or asbestos-like fibers and characterized by challenging diagnostics, poor response to current standard therapies, and dismal prognosis. MPM is difficult to distinguish from reactive pleural conditions using conventional imaging- and histopathology-based methodologies. Moreover, MPM displays one of the lowest somatic mutation burdens among cancers and is mainly driven by inactivation of specific tumor suppressor genes, rather than activating oncogene-mutations. These features complicate the implementation of targeted and immunological therapies for this cancer.

However, recent seminal comprehensive studies have enlightened the role played in MPM by important genetic, epigenetic, and immunological alterations as well as by the interplay between genetic cancer susceptibility and environmental factors. This allows delineating novel molecular and clinical subtypes, as well as promising diagnostic and therapeutic strategies for MPM.

This Special Issue, “Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma”, aims at collecting and welcomes original research articles, state-of-the-art review articles, and commentaries in this field.

Prof. Dr. Eric Santoni-Rugiu
Prof. Dr. Jens Benn Sørensen
Guest Editors

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

Malignant pleural mesothelioma
Molecular alterations
Novel biomarkers
Molecular subtypes
Genetic cancer susceptibility
Diagnosis
Prognosticators and predictors
Targeted therapy
Immunotherapy

Published Papers (7 papers)

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Research

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20 pages, 4691 KiB

Open AccessArticle

Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

by Eric Santoni-Rugiu, Maya Jeje Schuang Lü, Jan Nyrop Jakobsen, Linea Cecilie Melchior, Jesper Ravn and Jens Benn Sørensen

Int. J. Mol. Sci. 2021, 22(23), 12868; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312868 - 28 Nov 2021

Cited by 3 | Viewed by 2018

Abstract

Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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17 pages, 3346 KiB

Open AccessArticle

The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target

by Pınar Çakılkaya, Rikke Raagaard Sørensen, Henrik Jessen Jürgensen, Oliver Krigslund, Henrik Gårdsvoll, Christoffer F. Nielsen, Eric Santoni-Rugiu, Niels Behrendt and Lars H. Engelholm

Int. J. Mol. Sci. 2021, 22(21), 11452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111452 - 23 Oct 2021

Cited by 3 | Viewed by 2701

Abstract

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients’ asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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16 pages, 4065 KiB

Open AccessArticle

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

by Mara Bonelli, Rita Terenziani, Silvia Zoppi, Claudia Fumarola, Silvia La Monica, Daniele Cretella, Roberta Alfieri, Andrea Cavazzoni, Graziana Digiacomo, Maricla Galetti and Pier Giorgio Petronini

Int. J. Mol. Sci. 2020, 21(14), 5165; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145165 - 21 Jul 2020

Cited by 22 | Viewed by 3586

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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18 pages, 3042 KiB

Open AccessArticle

EIF4G1 and RAN as Possible Drivers for Malignant Pleural Mesothelioma

by Irene Dell’Anno, Marcella Barbarino, Elisa Barone, Antonio Giordano, Luca Luzzi, Maria Bottaro, Loredana Migliore, Silvia Agostini, Alessandra Melani, Ombretta Melaiu, Calogerina Catalano, Monica Cipollini, Roberto Silvestri, Alda Corrado, Federica Gemignani and Stefano Landi

Int. J. Mol. Sci. 2020, 21(14), 4856; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144856 - 09 Jul 2020

Cited by 10 | Viewed by 3113

Abstract

For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAN, SOD1, and THBS2) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression (“passenger genes”). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of EIF4G1 and RAN significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following RAN gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As EIF4G1 and RAN deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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Review

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37 pages, 984 KiB

Open AccessReview

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

by Ece Cakiroglu and Serif Senturk

Int. J. Mol. Sci. 2020, 21(17), 6342; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176342 - 01 Sep 2020

Cited by 16 | Viewed by 4929

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the mesothelial cells lining the pleural surface of the chest wall and lung. The etiology of MPM is strongly associated with prior exposure to asbestos fibers, and the median survival rate of the diagnosed patients is approximately one year. Despite the latest advancements in surgical techniques and systemic therapies, currently available treatment modalities of MPM fail to provide long-term survival. The increasing incidence of MPM highlights the need for finding effective treatments. Targeted therapies offer personalized treatments in many cancers. However, targeted therapy in MPM is not recommended by clinical guidelines mainly because of poor target definition. A better understanding of the molecular and cellular mechanisms and the predictors of poor clinical outcomes of MPM is required to identify novel targets and develop precise and effective treatments. Recent advances in the genomics and functional genomics fields have provided groundbreaking insights into the genomic and molecular profiles of MPM and enabled the functional characterization of the genetic alterations. This review provides a comprehensive overview of the relevant literature and highlights the potential of state-of-the-art genomics and functional genomics research to facilitate the development of novel diagnostics and therapeutic modalities in MPM. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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18 pages, 5535 KiB

Open AccessReview

Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review

by Vasiliki Panou and Oluf Dimitri Røe

Int. J. Mol. Sci. 2020, 21(12), 4327; https://doi.org/10.3390/ijms21124327 - 17 Jun 2020

Cited by 26 | Viewed by 3732

Abstract

Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos–gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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12 pages, 1101 KiB

Open AccessReview

Curcumin as an Anticancer Agent in Malignant Mesothelioma: A Review

by Alfonso Baldi, Antonio De Luca, Patrizia Maiorano, Costantino D’Angelo and Antonio Giordano

Int. J. Mol. Sci. 2020, 21(5), 1839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051839 - 07 Mar 2020

Cited by 24 | Viewed by 7027

Abstract

Malignant mesothelioma is an infrequent tumor that initiates from the mesothelial cells lining of body cavities. The great majority of mesotheliomas originate in the pleural cavity, while the remaining cases initiate in the peritoneal cavity, in the pericardial cavity or on the tunica vaginalis. Usually, mesotheliomas grow in a diffuse pattern and tend to enclose and compress the organs in the various body cavities. Mesothelioma incidence is increasing worldwide and still today, the prognosis is very poor, with a reported median survival of approximately one year from presentation. Thus, the development of alternative and more effective therapies is currently an urgent requirement. The aim of this review article was to describe recent findings about the anti-cancer activity of curcumin and some of its derivatives on mesotheliomas. The potential clinical implications of these findings are discussed. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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