bims-mesote 2023-06-25 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023‒06‒25
eight papers selected by
Laura Mannarino
Humanitas Research

Genomic and Transcriptomic Analyses of Malignant Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing.
Genes and Pathways Involved in the Progression of Malignant Pleural Mesothelioma: A Meta-analysis of Genome-Wide Expression Studies.
Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma.
Malignant pleural mesothelioma with constrictive pericarditis as the first manifestation: A case report.
The role of germline mutations in thoracic malignancies: between myth and reality.
Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis.
Comparison of immunohistochemical mesothelial biomarkers in paired biopsies and effusion cytology cell blocks from pleural mesothelioma.
SPC212 human mesothelioma cells underwent apoptosis, oxidative stress, and morphological deformation following Astaxanthin treatment.

Cancers (Basel). 2023 May 18. pii: 2813. [Epub ahead of print]15(10):

Genomic and Transcriptomic Analyses of Malignant Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing.

Alexander Laure, Angelica Rigutto, Michaela B Kirschner, Lennart Opitz, Linda Grob, Isabelle Opitz, Emanuela Felley-Bosco, Stefanie Hiltbrunner, Alessandra Curioni-Fontecedro.

  Cell lines are extensively used to study cancer biology. However, the use of highly passaged commercial cell lines has to be questioned, as they do not closely resemble the originating tumor. To understand the reliability of preclinical models for Malignant pleural mesothelioma (MPM) studies, we have performed whole transcriptome and whole exome analyses of fresh frozen MPM tumors and compared them to cell lines generated from these tumors, as well as commercial cell lines and a preclinical MPM mouse model. Patient-derived cell lines were generated from digested fresh tumors and whole exome sequencing was performed on DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor samples, corresponding patient-derived cell lines, and normal tissue. RNA sequencing libraries were prepared from 10 fresh frozen tumor samples, the 10 corresponding patient-derived cell lines, and 7 commercial cell lines. Our results identified alterations in tumor suppressor genes such as FBXW7, CDKN2A, CDKN2B, and MTAP, all known to drive MPM tumorigenesis. Patient-derived cell lines correlate to a high degree with their originating tumor. Gene expressions involved in multiple pathways such as EMT, apoptosis, myogenesis, and angiogenesis are upregulated in tumor samples when compared to patient-derived cell lines; however, they are downregulated in commercial cell lines compared to patient-derived cell lines, indicating significant differences between the two model systems. Our results show that the genome and transcriptome of tumors correlate to a higher degree with patient-derived cell lines rather than commercial cell lines. These results are of major relevance for the scientific community in regard to using cell lines as an appropriate model, resembling the pathway of interest to avoid misleading results for clinical applications.

Keywords:  genomic analysis; malignant pleural mesothelioma; patient-derived cell lines; preclinical models; transcriptomic analysis

DOI:  https://doi.org/10.3390/cancers15102813
Biochem Genet. 2023 Jun 22.

Genes and Pathways Involved in the Progression of Malignant Pleural Mesothelioma: A Meta-analysis of Genome-Wide Expression Studies.

Alejandro Mejia-Garcia, Diego A Bonilla, Claudia M Ramirez, Fabio A Escobar-Díaz, Alba Lucia Combita, Diego A Forero, Carlos Orozco.

  Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural tissue that lines the lungs and is mainly associated with long latency from asbestos exposure. This tumor has no effective therapeutic opportunities nowadays and has a very low five-year survival rate. In this sense, identifying molecular events that trigger the development and progression of this tumor is highly important to establish new and potentially effective treatments. We conducted a meta-analysis of genome-wide expression studies publicly available at the Gene Expression Omnibus (GEO) and ArrayExpress databases. The differentially expressed genes (DEGs) were identified, and we performed functional enrichment analysis and protein-protein interaction networks (PPINs) to gain insight into the biological mechanisms underlying these genes. Additionally, we constructed survival prediction models for selected DEGs and predicted the minimum drug inhibition concentration of anticancer drugs for MPM. In total, 115 MPM tumor transcriptomes and 26 pleural tissue controls were analyzed. We identified 1046 upregulated DEGs in the MPM samples. Cellular signaling categories in tumor samples were associated with the TNF, PI3K-Akt, and AMPK pathways. The inflammatory response, regulation of cell migration, and regulation of angiogenesis were overrepresented biological processes. Expression of SOX17 and TACC1 were associated with reduced survival rates. This meta-analysis identified a list of DEGs in MPM tumors, cancer-related signaling pathways, and biological processes that were overrepresented in MPM samples. Some therapeutic targets to treat MPM are suggested, and the prognostic potential of key genes is shown.

Keywords:  Differentially expressed genes; Genome-wide expression studies; Malignant pleural mesothelioma; Meta-analysis

DOI:  https://doi.org/10.1007/s10528-023-10426-5
Front Immunol. 2023 ;14 1151194

Complement protein C1q stimulates hyaluronic acid degradation via gC1qR/HABP1/p32 in malignant pleural mesothelioma.

Andrea Balduit, Romana Vidergar, Paola Zacchi, Alessandro Mangogna, Chiara Agostinis, Micaela Grandolfo, Cristina Bottin, Francesco Salton, Paola Confalonieri, Andrea Rocca, Fabrizio Zanconati, Marco Confalonieri, Uday Kishore, Berhane Ghebrehiwet, Roberta Bulla.

  Complement component C1q can act as a pro-tumorigenic factor in the tumor microenvironment (TME). The TME in malignant pleural mesothelioma (MPM) is rich in C1q and hyaluronic acid (HA), whose interaction enhances adhesion, migration and proliferation of malignant cells. HA-bound C1q is also capable of modulating HA synthesis. Thus, we investigated whether HA-C1q interaction would affect HA degradation, analyzing the main degradation enzymes, hyaluronidase (HYAL)1 and HYAL2, and a C1q receptor candidate. We first proceeded with the characterization of HYALs in MPM cells, especially HYAL2, since bioinformatics survival analysis revealed that higher HYAL2 mRNA levels have an unfavorable prognostic index in MPM patients. Interestingly, Real-Time quantitative PCR, flow cytometry and Western blot highlighted an upregulation of HYAL2 after seeding of primary MPM cells onto HA-bound C1q. In an attempt to unveil the receptors potentially involved in HA-C1q signaling, a striking co-localization between HYAL2 and globular C1q receptor/HABP1/p32 (gC1qR) was found by immunofluorescence, surface biotinylation and proximity ligation assays. RNA interference experiments revealed a potentially regulatory function exerted by gC1qR on HYAL2 expression, since C1QBP (gene for gC1qR) silencing unexpectedly caused HYAL2 downregulation. In addition, the functional blockage of gC1qR by a specific antibody hindered HA-C1q signaling and prevented HYAL2 upregulation. Thus, C1q-HA interplay is responsible for enhanced HYAL2 expression, suggesting an increased rate of HA catabolism and the release of pro-inflammatory and pro-tumorigenic HA fragments in the MPM TME. Our data support the notion of an overall tumor-promoting property of C1q. Moreover, the overlapping localization and physical interaction between HYAL2 and gC1qR suggests a potential regulatory effect of gC1qR within a putative HA-C1q macromolecular complex.

Keywords:  C1q; HYAL2; gC1qR/HABP1/p32; hyaluronic acid; hyaluronidase; malignant pleural mesothelioma; reactive oxygen species

DOI:  https://doi.org/10.3389/fimmu.2023.1151194
Clin Case Rep. 2023 Jun;11(6): e7555

Malignant pleural mesothelioma with constrictive pericarditis as the first manifestation: A case report.

Cheng-Peng He, Di-Wei Tu, Ting-Wei Zhang, Qian Zhang, Qiang Zhang, Di Kang, Ying-Ying Wang, Ying-Ying Li, Bin Zhang, Sha-Sha Han, Hong-Bo Li.

  Pleural mesothelioma (PM) with pericardial involvement is extremely rare. We now report a rare case of malignant PM with constrictive pericarditis as the first presentation. A 59-year-old male diagnosed with constrictive pericarditis underwent pericardiectomy and pericardial pathology revealed mesothelial hyperplasia. Eight months after surgery, the patient was admitted to the hospital with chest tightness and wheezing for 5 days. Computed tomography scan of the chest showed a left lung expansion insufficiency, limited bilateral pleural thickening, pericardial thickening with a small amount of pericardial effusion, and multiple enlarged lymph nodes in the mediastinum, bilateral supraclavicular fossa, bilateral cervical roots, and right axilla. The pleural malignancy should be possibly considered. Pathology after pleural puncture showed malignant PM. Pathology after left supraclavicular lymph node puncture biopsy showed metastatic malignant mesothelioma. The diagnosis of this patient was clear. Although malignant PM rarely involves the pericardial constriction, we cannot ignore the fact that malignant PM involves the pericardium. The patient has been diagnosed with constrictive pericarditis, accompanied by pleural thickening and pleural effusion. Without other pathogenic factors, pleural biopsy should be aggressively performed in patients with constrictive pericarditis to determine the cause.

Keywords:  constrictive pericarditis; malignant pleural mesothelioma; pericardium

DOI:  https://doi.org/10.1002/ccr3.7555
J Thorac Oncol. 2023 Jun 16. pii: S1556-0864(23)00612-3. [Epub ahead of print]

The role of germline mutations in thoracic malignancies: between myth and reality.

Farinea Giovanni, Crespi Veronica, Listì Angela, Righi Luisella, Bironzo Paolo, Merlini Alessandra, Malapelle Umberto, Novello Silvia, Scagliotti Giorgio Vittorio, Passiglia Francesco.

  Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely been explored. However, the recent introduction of next-generation sequencing (NGS)-based tumor molecular profiling in the real-word setting enabled us to deeply characterize the genetic background of lung cancer patients with or without smoking-related history, increasing the likelihood of detecting germline mutations with potential prevention as well as treatment implications. Pathogenic germline variants have been detected in 2-3% of non-small cell lung cancer patients undergoing NGS analysis, while the proportion of germline mutations associated with the development of pleural mesothelioma widely varies across different studies, ranging between 5 and 10%. This review provides an updated summary of emerging evidence about germline mutations in thoracic malignancies, focusing on pathogenetic mechanisms, clinical features, therapeutic implications as well as screening recommendations for high-risk individuals.

Keywords:  genetic testing; germline mutations; lung cancer; malignant pleural mesothelioma; next-generation sequencing; thoracic malignancies

DOI:  https://doi.org/10.1016/j.jtho.2023.05.028
Thorac Cancer. 2023 Jun 21.

Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis.

Berta Mosleh, Karin Schelch, Thomas Mohr, Thomas Klikovits, Christina Wagner, Lukas Ratzinger, Yawen Dong, Katharina Sinn, Alexander Ries, Walter Berger, Bettina Grasl-Kraupp, Konrad Hoetzenecker, Viktoria Laszlo, Balazs Dome, Balazs Hegedus, Marko Jakopovic, Mir Alireza Hoda, Michael Grusch.

  BACKGROUND: Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker.METHODS: FGF18 mRNA expression was analyzed by real-time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters.
RESULTS: FGF18 showed high mRNA expression in PM and PM-derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed.
CONCLUSIONS: FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation.

Keywords:  FGF18; biomarker; fibroblast growth factor 18; pleural mesothelioma

DOI:  https://doi.org/10.1111/1759-7714.15004
Cytopathology. 2023 Jun 19.

Comparison of immunohistochemical mesothelial biomarkers in paired biopsies and effusion cytology cell blocks from pleural mesothelioma.

Mohammed S I Mansour, Adela Huseinzade, Tomas Seidal, Kim Hejny, Athar Maty, Fereshteh Taheri-Eilagh, Ulrich Mager, Annika Dejmek, Katalin Dobra, Hans Brunnström.

  OBJECTIVE: Traditionally, the diagnosis of pleural mesothelioma is based on histological material. Minimally invasive effusion cytology specimens are an alternative that, like biopsies, require ancillary analyses. Validation of immunohistochemical (IHC) analyses on cytology, including the surrogate markers for molecular alterations BAP1 and MTAP, is of interest.METHODS: IHC for eight different markers was performed on 59 paired formalin-fixed, paraffin-embedded pleural biopsies and pleural effusion cell blocks with mesothelioma. Immunoreactivity in ≥10% of tumour cells was considered positive/preserved. The concordance between histological and cytological materials was assessed.
RESULTS: The overall percentage of agreement between the histological epithelioid component in 58 biopsies and paired cell blocks was 93% for calretinin, 98% for CK5, 97% for podoplanin, 90% for WT1, 86% for EMA, 100% for desmin, 91% for BAP1, and 72% for MTAP. For 11 cases with biphasic or sarcomatoid histology, the concordance between cytology and the histological sarcomatoid component was low for calretinin, CK5, and WT1 (all ≤45%). For the whole cohort, loss of both BAP1 and MTAP was seen in 40% while both markers were preserved in 11% of the biopsies for epithelioid histology. The corresponding numbers were 54% and 8%, respectively, for the paired cell blocks.
CONCLUSIONS: Generally, a high concordance for IHC staining was seen between paired biopsies and pleural effusion cell blocks from mesotheliomas, but the somewhat lower agreement for WT1, EMA, and especially MTAP calls for further investigation and local quality assurance. The lower concordance for the sarcomatoid subtype for some markers may indicate biological differences.

Keywords:  BAP1; CK5; EMA; MTAP; calretinin; podoplanin

DOI:  https://doi.org/10.1111/cyt.13265
J Biochem Mol Toxicol. 2023 Jun 22. e23415

SPC212 human mesothelioma cells underwent apoptosis, oxidative stress, and morphological deformation following Astaxanthin treatment.

Sedat Kaçar, Tuğba Semerci Sevimli, Varol Şahintürk.

  Astaxanthin (ASX) is one of the keto-carotenoids, which is biologically more active than other counterparts. Besides its variety of beneficial effects, it was reported to exert anticancer effects. Despite its utilization against different cancer types, the effect of ASX on mesothelioma has yet to be well-studied. In this study, our goal is to ascertain how ASX will affect SPC212 human mesothelioma cells. First, the effective doses of ASX against SPC212 cells were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Thereafter, with flow cytometry analysis, Annexin-V and caspase 3/7 assay were implemented for the evaluation of apoptotic cell death and an oxidative stress test was carried out to determine how the free radicals changed. Ultimately, the cells' morphology was examined under a light microscope. The effective doses of ASX were found as 50, 100, and 200 µM. In the Annexin V assay, the total apoptosis increased to around 12%, 30%, and 45% with increasing doses of ASX. In the caspase 3/7 assay, the total apoptosis was around 25% and 38% at 100 and 200 µM. In oxidative stress analysis, reactive oxygen species-positive cells rose from 4.54 at the lowest dose to 86.95 at the highest dose. In morphological analysis, cellular shrinkage, decrease in cell density, swelling and vacuolations in some cells, membrane blebbing, and apoptotic bodies are observed in ASX-treated cells. To conclude, the current study provided insights into the efficacy and effects of ASX against SPC212 mesothelioma cells regarding morphology, proliferation, and cell death for future studies.

Keywords:  Astaxanthin; SPC212; apoptosis; cytotoxicity; malignant pleural mesothelioma

DOI:  https://doi.org/10.1002/jbt.23415