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Molecular Mechanisms and Therapies of Malignant Mesothelioma 2.0
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Molecular Mechanisms and Therapies of Malignant Mesothelioma 2.0

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 July 2024) | Viewed by 8254

Special Issue Editor

Dr. Giovanni Cugliari

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals

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 (4 papers)

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Research

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13 pages, 1804 KiB  
Article
Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6
by Mario Cioce, Veronica Gatti, Fabiana Napolitano, Noemi Maria Giorgiano, Andrea Marra, Giuseppe Portella, Alfonso Fiorelli, Francesca Pentimalli and Vito Michele Fazio
Int. J. Mol. Sci. 2024, 25(10), 5355; https://doi.org/10.3390/ijms25105355 - 14 May 2024
Viewed by 1682
Abstract
Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM [...] Read more.
Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma 2.0)
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17 pages, 902 KiB  
Article
Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma
by Cita Zupanc, Alenka Franko, Danijela Štrbac, Viljem Kovač, Vita Dolžan and Katja Goričar
Int. J. Mol. Sci. 2024, 25(1), 190; https://doi.org/10.3390/ijms25010190 - 22 Dec 2023
Cited by 2 | Viewed by 1117
Abstract
Calretinin is a promising diagnostic biomarker for malignant mesothelioma (MM), but less is known about its prognostic role. Our aim was to evaluate the association between serum calretinin concentration or genetic factors and the survival or outcome of cisplatin-based chemotherapy in MM. Our [...] Read more.
Calretinin is a promising diagnostic biomarker for malignant mesothelioma (MM), but less is known about its prognostic role. Our aim was to evaluate the association between serum calretinin concentration or genetic factors and the survival or outcome of cisplatin-based chemotherapy in MM. Our study included 265 MM patients. Serum calretinin concentration was determined using ELISA. Patients were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1, and SEPTIN7 using competitive allele-specific PCR. Nonparametric tests, logistic regression, and survival analysis were used for statistical analysis. Higher serum calretinin concentration was associated with shorter progression-free (PFS) (HR = 1.18 (1.02–1.37), p = 0.023) and overall survival (OS) (HR = 1.20 (1.03–1.41), p = 0.023), but the association was not significant after adjusting for clinical factors (HR = 1.05 (0.85–1.31), p = 0.653 and HR = 1.06 (0.84–1.34), p = 0.613, respectively). SEPTIN7 rs3801339 and MIR335 rs3807348 were associated with survival even after adjustment (HR = 1.76 (1.17–2.64), p = 0.007 and HR = 0.65 (0.45–0.95), p = 0.028, respectively). Calretinin concentration was higher in patients who progressed after treatment with cisplatin-based chemotherapy (1.68 vs. 0.45 ng/mL, p = 0.001). Calretinin concentration above 0.89 ng/mL was associated with shorter PFS and OS from the start of chemotherapy (HR = 1.88 (1.28–2.77), p = 0.001 and HR = 1.91 (1.22–2.97), p = 0.004, respectively), even after adjusting for clinical factors (p < 0.05). MIR335 rs3807348 was associated with a better response to chemotherapy (OR = 2.69 (1.17–6.18), p = 0.020). We showed that serum calretinin is associated with survival and chemotherapy treatment outcomes in MM and could serve as a predictive biomarker. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma 2.0)
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12 pages, 64047 KiB  
Article
One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy
by Thomas Hager, Sabrina Borchert, Michael Wessolly, Alexander Mathilakathu, Elena Mairinger, Jens Kollmeier, Thomas Mairinger, Balazs Hegedus, Kristina Greimelmaier, Jeremias Wohlschlaeger, Ken Herrmann and Fabian Dominik Mairinger
Int. J. Mol. Sci. 2023, 24(7), 6356; https://doi.org/10.3390/ijms24076356 - 28 Mar 2023
Cited by 2 | Viewed by 2017
Abstract
Malignant pleural mesothelioma (MPM) is a mainly asbestos-related tumour associated with a very poor prognosis. Therapeutic approaches include multimodal therapy and chemotherapeutics, with cisplatin being the drug of choice, but response rates of only up to 14% indicate very poor outcomes. Effective treatment [...] Read more.
Malignant pleural mesothelioma (MPM) is a mainly asbestos-related tumour associated with a very poor prognosis. Therapeutic approaches include multimodal therapy and chemotherapeutics, with cisplatin being the drug of choice, but response rates of only up to 14% indicate very poor outcomes. Effective treatment options are lacking. Besides the diagnostic usage of radioligands in positron emission tomography (PET)/computed tomography (CT), the endo-radioligand therapy with Lu177 has been proven as a powerful tool in cancer therapy. Mesothelin (MSLN) and C-XC chemokine receptor 4 (CXCR4) are membrane-bound proteins, expressed in certain cancers, and thus are promising targets for endo-radiotherapy. A significant portion of high MSLN- or CXCR4-expressing tumors within the MPM may open the field for this sophisticated treatment approach in the near future. Formalin-fixed, paraffin-embedded (FFPE) tumour specimens from 105 patients suffering from MPM and treated at the Lung Cancer Centre of Essen and at the Helios Klinikum Emil von Behring Berlin were screened. The tumour samples were arranged in tissue microarrays. We immunohistochemically stained the tumour samples against MSLN and CXCR4. The protein expressions of the stainings were scored by a pathologist by using a semiquantitative method. The data obtained were correlated with the clinical outcome. Overall, 77.1% of the analysed tumours showed CXCR4 protein expression (25.7% of them at high expression level (Score 3)). 48.6% of all samples showed an overall strong staining (Score ≥ 2), 59% of the investigated tumours showed MSLN protein expression (10.5% of them at high expression (Score 3)), and 36.2% of all samples showed an overall strong staining (Score ≥ 2). Our results show significant tissue expression levels, for both CXCR4 and MSLN protein, in a major portion of clinical MPM samples. One-third of patients showed outstanding immunoexpression of at least one of these markers, making them interesting candidates for radioligand-based PET/CT diagnostics and follow-up and furthermore may profit from endo-radiotherapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma 2.0)
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Review

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22 pages, 363 KiB  
Review
Improvements in Systemic Therapies for Advanced Malignant Mesothelioma
by Chiara Deiana, Francesca Fabbri, Simona Tavolari, Andrea Palloni and Giovanni Brandi
Int. J. Mol. Sci. 2023, 24(13), 10415; https://doi.org/10.3390/ijms241310415 - 21 Jun 2023
Cited by 4 | Viewed by 2602
Abstract
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy associated with poor prognosis and a 5-year survival rate of 12%. Many drugs have been tested over the years with conflicting results. The aim of this review is to provide an overview of [...] Read more.
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy associated with poor prognosis and a 5-year survival rate of 12%. Many drugs have been tested over the years with conflicting results. The aim of this review is to provide an overview of current therapies in MPM and how to best interpret the data available on these drugs. Furthermore, we focused on promising treatments under investigation, such as immunotherapy with targets different from anti-PD-1/PD-L1 inhibitors, vaccines, target therapies, and metabolism-based strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Malignant Mesothelioma 2.0)
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