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Molecular Mechanisms and Therapies of Malignant 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 Oncology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 25294

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Dr. Giovanni Cugliari

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Guest Editor

Department of Medical Sciences, University of Turin, 10126 Turin, Italy
Interests: epigenetics; DNA methylation; cancer; statistical methods; artificial intelligence; machine learning; multi-omics analyses
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Special Issue Information

Dear Colleagues,

Malignant mesothelioma (MM) is a rare and aggressive neoplasm related to exposure to asbestos with high impact in public health given its late diagnosis, dismal prognosis, and lack of current efficient therapies.

Important insights have recently been made in the understanding of MM’s complex biology and the cancer development process. Examples of these include the identification of new biomarkers and the deciphering of gene–environment interactions, deregulated pathways, altered expression of miRNAs, differences in DNA methylation, proteomic composition or metabolic profile, but have not been established in clinical routine use yet.

Regarding treatment, extended pleurectomy/decortication, extrapleural pneumonectomy (EPP), intensity-modulated radiotherapy, targeted therapies, immunotherapy, and vaccination are considered as new promising strategies and deserve further investigations. Overall, there has not been a real breakthrough in the treatment of MM. Further research and clinical trials are needed to evaluate outcome and to identify new potential treatment candidates.

Given these improvements, new risk assessment procedures and therapeutic strategies are being explored in order to 1) introducing interaction between genetic and epigenetic related variables (as for example bio aging indicators) to better characterize the MM pathway, 2) evaluate new statistical/ML approaches in order to investigate integromic approaches including more than one omics dataset simultaneously.

This Special Issue will highlight all these aspects.

Dr. Giovanni Cugliari
Guest Editor

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Keywords

malignant mesothelioma
asbestos exposure
carcinogenesis
diagnostic
prognosis
inherited mutations
biomarker
microRNA
DNA methylation
metabolomics
proteomics
aging
immunotherapy
chemotherapy
combination therapy

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 189 KiB

Open AccessEditorial

FKBP5, a Modulator of Stress Responses Involved in Malignant Mesothelioma: The Link between Stress and Cancer

by Giovanni Cugliari

Int. J. Mol. Sci. 2023, 24(9), 8183; https://doi.org/10.3390/ijms24098183 - 3 May 2023

Cited by 1 | Viewed by 1871

Abstract

Malignant pleural mesothelioma (MPM) is a rare tumour characterized by a long latency period after asbestos exposure and poor survival [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

Research

Jump to: Editorial, Review

14 pages, 1368 KiB

Open AccessArticle

Prognostic Value of EMT Gene Signature in Malignant Mesothelioma

by Licun Wu, Kosuke Yoshihara, Hana Yun, Saraf Karim, Nastaran Shokri, Fatemeh Zaeimi, H. S. Jeffrey Man, Amin Zia, Emanuela Felley-Bosco and Marc de Perrot

Int. J. Mol. Sci. 2023, 24(5), 4264; https://doi.org/10.3390/ijms24054264 - 21 Feb 2023

Cited by 6 | Viewed by 3011

Abstract

Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial–mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-β signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-β1/TGFBR1 pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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18 pages, 6994 KiB

Open AccessArticle

Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells

by Tatyana Chernova, Stefano Grosso, Xiao-Ming Sun, Angela Rubio Tenor, Joaquin Zacarias Cabeza, Andrew Craxton, Emily L. Self, Apostolos Nakas, Kelvin Cain, Marion MacFarlane and Anne E. Willis

Int. J. Mol. Sci. 2022, 23(20), 12469; https://doi.org/10.3390/ijms232012469 - 18 Oct 2022

Cited by 5 | Viewed by 2522

Abstract

Malignant mesothelioma is an aggressive tumour of the pleura (MPM) or peritoneum with a clinical presentation at an advanced stage of the disease. Current therapies only marginally improve survival and there is an urgent need to identify new treatments. Carcinoma-associated fibroblasts (CAFs) represent the main component of a vast stroma within MPM and play an important role in the tumour microenvironment. The influence of CAFs on cancer progression, aggressiveness and metastasis is well understood; however, the role of CAF-derived extracellular vesicles (CAF-EVs) in the promotion of tumour development and invasiveness is underexplored. We purified CAF-EVs from MPM-associated cells and healthy dermal human fibroblasts and examined their effect on cell proliferation and motility. The data show that exposure of healthy mesothelial cells to EVs derived from CAFs, but not from normal dermal human fibroblasts (NDHF) resulted in activating pro-oncogenic signalling pathways and increased proliferation and motility. Consistent with its role in suppressing Yes-Associated Protein (YAP) activation (which in MPM is a result of Hippo pathway inactivation), treatment with Simvastatin ameliorated the pro-oncogenic effects instigated by CAF-EVs by mechanisms involving both a reduction in EV number and changes in EV cargo. Collectively, these data determine the significance of CAF-derived EVs in mesothelioma development and progression and suggest new targets in cancer therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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13 pages, 2330 KiB

Open AccessArticle

Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma

by Darya Karatkevich, Haibin Deng, Yanyun Gao, Emilio Flint, Ren-Wang Peng, Ralph Alexander Schmid, Patrick Dorn and Thomas Michael Marti

Int. J. Mol. Sci. 2022, 23(19), 11949; https://doi.org/10.3390/ijms231911949 - 8 Oct 2022

Cited by 3 | Viewed by 2309

Abstract

Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect γH2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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16 pages, 2000 KiB

Open AccessArticle

Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma

by Iacopo Gesmundo, Francesca Pedrolli, Nicoletta Vitale, Alessia Bertoldo, Giulia Orlando, Dana Banfi, Giuseppina Granato, Ramesh Kasarla, Federico Balzola, Silvia Deaglio, Renzhi Cai, Wei Sha, Mauro Papotti, Ezio Ghigo, Andrew V. Schally and Riccarda Granata

Int. J. Mol. Sci. 2022, 23(19), 11248; https://doi.org/10.3390/ijms231911248 - 24 Sep 2022

Cited by 4 | Viewed by 2474

Abstract

Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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11 pages, 2017 KiB

Open AccessArticle

Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study

by Laura Mannarino, Lara Paracchini, Federica Pezzuto, Gheorghe Emilian Olteanu, Laura Moracci, Luca Vedovelli, Irene De Simone, Cristina Bosetti, Monica Lupi, Rosy Amodeo, Alessia Inglesi, Maurizio Callari, Serena Penpa, Roberta Libener, Sara Delfanti, Antonina De Angelis, Alberto Muzio, Paolo Andrea Zucali, Paola Allavena, Giovanni Luca Ceresoli, Sergio Marchini, Fiorella Calabrese, Maurizio D’Incalci and Federica Grosso Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(10), 5786; https://doi.org/10.3390/ijms23105786 - 21 May 2022

Cited by 14 | Viewed by 2998

Abstract

Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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16 pages, 2405 KiB

Open AccessArticle

Forchlorfenuron and Novel Analogs Cause Cytotoxic Effects in Untreated and Cisplatin-Resistant Malignant Mesothelioma-Derived Cells

by Thomas Henzi, Kim-Long Diep, Anne Oberson, Valerie Salicio, Christian G. Bochet and Beat Schwaller

Int. J. Mol. Sci. 2022, 23(7), 3963; https://doi.org/10.3390/ijms23073963 - 2 Apr 2022

Cited by 4 | Viewed by 2075

Abstract

Malignant mesothelioma (MM) is a currently incurable, aggressive cancer derived from mesothelial cells, most often resulting from asbestos exposure. The current first-line treatment in unresectable MM is cisplatin/pemetrexed, which shows very little long-term effectiveness, necessitating research for novel therapeutic interventions. The existing chemotherapies often act on the cytoskeleton, including actin filaments and microtubules, but recent advances indicate the ‘fourth’ form consisting of the family of septins, representing a novel target. The septin inhibitor forchlorfenuron (FCF) and FCF analogs inhibit MM cell growth in vitro, but at concentrations which are too high for clinical applications. Based on the reported requirement of the chloride group in the 2-position of the pyridine ring of FCF for MM cell growth inhibition and cytotoxicity, we systematically investigated the importance (cell growth-inhibiting capacity) of the halogen atoms fluorine, chlorine, bromine and iodine in the 2- or 3-position of the pyridine ring. The MM cell lines ZL55, MSTO-211H, and SPC212, and—as a control—immortalized Met-5A mesothelial cells were used. The potency of the various halogen substitutions in FCF was mostly correlated with the atom size (covalent radius); the small fluoride analogs showed the least effect, while the largest one (iodide) most strongly decreased the MTT signals, in particular in MM cells derived from epithelioid MM. In the latter, the strongest effects in vitro were exerted by the 2-iodo and, unexpectedly, the 2-trifluoromethyl (2-CF₃) FCF analogs, which were further tested in vivo in mice. However, FCF-2-I and, more strongly, FCF-2-CF₃ caused rapidly occurring strong symptoms of systemic toxicity at doses lower than those previously obtained with FCF. Thus, we investigated the effectiveness of FCF (and selected analogs) in vitro in MM cells which were first exposed to cisplatin. The slowly appearing population of cisplatin-resistant cells was still susceptible to the growth-inhibiting/cytotoxic effect of FCF and its analogs, indicating that cisplatin and FCF target non-converging pathways in MM cells. Thus, a combination therapy of cisplatin and FCF (analogs) might represent a new avenue for the treatment of repopulating chemo-resistant MM cells in this currently untreatable cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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15 pages, 3134 KiB

Open AccessArticle

Molecular Radiotherapy with ¹⁷⁷Lu-Immunoliposomes Induces Cytotoxicity in Mesothelioma Cancer Stem Cells In Vitro

by Tao Huang, Jae Sam Lee, Alexander L. Klibanov and Jiang He

Int. J. Mol. Sci. 2022, 23(7), 3914; https://doi.org/10.3390/ijms23073914 - 1 Apr 2022

Cited by 2 | Viewed by 2171

Abstract

Malignant mesothelioma (MM) is a lethal tumor originating in the mesothelium with high chemotherapeutic resistance. Cancer stem cells (CSCs) persist in tumors and are critical targets responsible for tumor resistance and recurrence. The identification and characterization of CSCs may help develop effective treatment for MM. The objective of this study was to evaluate the therapeutic effect of molecular targeted radiotherapy by ¹⁷⁷Lu-labeled immunoliposomes (¹⁷⁷Lu-ILs) on CSCs of mesothelioma. MM CSCs were sorted based on CD26/CD24 expression level and their functional significances were established by small interference RNA. CSC potential of MM was evaluated for drug resistance, cell invasion, and cell growth rate in vitro. CSC metabolism was evaluated with the uptake of ¹⁸F-FDG. Therapeutic effects of ¹⁷⁷Lu-labeled immunoliposomes targeting CD26 and CD24 were evaluated in vitro through proliferation and apoptotic assays. CSCs sorted from H28 cells exhibited significant drug resistance and enhanced proliferative activity as well as increased metabolism indicated by higher ¹⁸F-FDG uptake. Treatment with ¹⁷⁷Lu-ILs, compared with ¹⁷⁷Lu-CL and ILs, showed enhanced therapeutic effects on inhibition of proliferation, up-regulation of apoptosis, and suppression of CD26 and CD24 expression. Thus, our results suggest that molecular radiotherapy targeting both CD26 and CD24 could be a promising approach for CSC-targeting therapy for MM. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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Review

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25 pages, 1096 KiB

Open AccessReview

Target Therapy in Malignant Pleural Mesothelioma: Hope or Mirage?

by Federica Borea, Marika A. Franczak, Maria Garcia, Matteo Perrino, Nadia Cordua, Ryszard T. Smolenski, Godefridus J. Peters, Rafal Dziadziuszko, Armando Santoro, Paolo A. Zucali and Elisa Giovannetti

Int. J. Mol. Sci. 2023, 24(11), 9165; https://doi.org/10.3390/ijms24119165 - 23 May 2023

Cited by 8 | Viewed by 4441

Abstract

Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring systemic treatment. Chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care for approximately 20 years, without any relevant therapeutic advance until the introduction of immune checkpoint inhibitors. Nevertheless, the prognosis remains poor, with an average survival of only 18 months. Thanks to a better understanding of the molecular mechanisms underlying tumor biology, targeted therapy has become an essential therapeutic option in several solid malignancies. Unfortunately, most of the clinical trials evaluating potentially targeted drugs for MPM have failed. This review aims to present the main findings of the most promising targeted therapies in MPM, and to explore possible reasons leading to treatments failures. The ultimate goal is to determine whether there is still a place for continued preclinical/clinical research in this area. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma)

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