bims-mesote Biomed News
on Mesothelioma
Issue of 2023–05–21
eight papers selected by
Laura Mannarino, Humanitas Research
  1. FKBP5, a Modulator of Stress Responses Involved in Malignant Mesothelioma: The Link between Stress and Cancer.
  2. A Novel Two-Gene Expression-Based Prognostic Score in Malignant Pleural Mesothelioma.
  3. Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential.
  4. Trimodality therapy of malignant pleural mesothelioma with helical tomotherapy.
  5. NF2 alteration in mesothelioma.
  6. Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma.
  7. The clinicopathological significance of TOP2A expression in malignant peritoneal mesothelioma.
  8. The crystal structure of the killer fibre erionite from Tuzköy (Cappadocia, Turkey).
  1. Int J Mol Sci. 2023 May 03. pii: 8183. [Epub ahead of print]24(9):
    FKBP5, a Modulator of Stress Responses Involved in Malignant Mesothelioma: The Link between Stress and Cancer.
    Giovanni Cugliari.
      Malignant pleural mesothelioma (MPM) is a rare tumour characterized by a long latency period after asbestos exposure and poor survival [...].
    DOI:  https://doi.org/10.3390/ijms24098183
  2. Diagnostics (Basel). 2023 Apr 26. pii: 1556. [Epub ahead of print]13(9):
    A Novel Two-Gene Expression-Based Prognostic Score in Malignant Pleural Mesothelioma.
    Velizar Shivarov, Georgi Blazhev, Angel Yordanov.
       BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare cancer type with an increasing incidence worldwide. We aimed to develop a rational gene expression-based prognostic score in MPM using publicly available datasets.
    METHODS: We developed and validated a two-gene prognostic score (2-PS) using three independent publicly available gene expression datasets. The 2-PS was built using the Robust Likelihood-Based Survival Modeling with Microarray Data method.
    RESULTS: We narrowed down the model building to the analysis of 179 genes, which have been shown previously to be of importance to MPM development. Our statistical approach showed that a model including two genes (GOLT1B and MAD2L1) was the best predictor for overall survival (OS) (p < 0.0001). The binary score based on the median of the continuous score stratified the patients into low and high score groups and also showed statistical significance in uni- and multivariate models. The 2-PS was validated using two independent transcriptomic datasets. Furthermore, gene set enrichment analysis using training and validation datasets showed that high score patients had distinct gene expression profiles. Our 2-PS also showed a correlation with the estimated infiltration by some immune cell fractions such as CD8+ T cells and M1/2 macrophages. Finally, 2-PS correlated with sensitivity or resistance to some commonly used chemotherapeutic drugs.
    CONCLUSION: This is the first study to demonstrate good performance of only two-gene expression-based prognostic scores in MPM. Our initial approach for features selection allowed for an increased likelihood for the predictive value of the developed score, which we were also able to demonstrate.
    Keywords:  gene expression; mesothelioma; prediction; prognosis; score
    DOI:  https://doi.org/10.3390/diagnostics13091556
  3. Cancers (Basel). 2023 Apr 18. pii: 2364. [Epub ahead of print]15(8):
    Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential.
    Tamkin Ahmadzada, Abhishek Vijayan, Fatemeh Vafaee, Ali Azimi, Glen Reid, Stephen Clarke, Steven Kao, Georges E Grau, Elham Hosseini-Beheshti.
      Pleural mesothelioma, previously known as malignant pleural mesothelioma, is an aggressive and fatal cancer of the pleura, with one of the poorest survival rates. Pleural mesothelioma is in urgent clinical need for biomarkers to aid early diagnosis, improve prognostication, and stratify patients for treatment. Extracellular vesicles (EVs) have great potential as biomarkers; however, there are limited studies to date on their role in pleural mesothelioma. We conducted a comprehensive proteomic analysis on different EV populations derived from five pleural mesothelioma cell lines and an immortalized control cell line. We characterized three subtypes of EVs (10 K, 18 K, and 100 K), and identified a total of 4054 unique proteins. Major differences were found in the cargo between the three EV subtypes. We show that 10 K EVs were enriched in mitochondrial components and metabolic processes, while 18 K and 100 K EVs were enriched in endoplasmic reticulum stress. We found 46 new cancer-associated proteins for pleural mesothelioma, and the presence of mesothelin and PD-L1/PD-L2 enriched in 100 K and 10 K EV, respectively. We demonstrate that different EV populations derived from pleural mesothelioma cells have unique cancer-specific proteomes and carry oncogenic cargo, which could offer a novel means to extract biomarkers of interest for pleural mesothelioma from liquid biopsies.
    Keywords:  biomarkers; exosomes; extracellular vesicles; malignant pleural mesothelioma; microvesicles; oncosomes
    DOI:  https://doi.org/10.3390/cancers15082364
  4. North Clin Istanb. 2023 ;10(2): 172-180
    Trimodality therapy of malignant pleural mesothelioma with helical tomotherapy.
    Hazan Ozyurt, Sevim Ozdemir, Bedriye Dogan, Gun Gunalp, Ayse Sevgi Ozden.
       OBJECTIVE: The purpose of this study was to determine the efficacy and tolerability of hemithoracic radiotherapy implemented with helical tomotherapy (HTT) in malignant pleural mesothelioma (MPM) patients.
    METHODS: Between October 2018 and December 2020, data from 11 MPM patients who received trimodality therapy, including lung-sparing surgery (pleurectomy-decortication, P/D), adjuvant chemotherapy (cisplatin+ pemetrexed), and radiotherapy, were retrospectively reviewed. HTT was used to deliver a total of 30 Gy, 50-54 Gy or 59.4-60 Gy to R2 disease with 1.8-2 Gy daily doses. Descriptive data are presented in number (percentage) or median (minimum- maximum). The Kaplan-Meier method was used to calculate survival data. In patients with toxicities, the risk organ doses were compared using the Mann-Whitney U test.
    RESULTS: The median follow-up was 20.5 (12-30) months. Two-year local control, disease-free, and overall survival rates were 48.5%, 49%, and 77.9%, respectively. The median prescribed dose for planning target volume (PTV) was 50.4±8.7 (30-60) Gy. Mean dose (Dmean) of total lung was 19.9±6 (10.4-26) Gy; the V20 (%) of ipsilateral and contralateral lungs were 89.±11.2 (62.7-100) and 0.7±2.1 (0.49-5.9), respectively. Esophageal Dmean and maximum doses (Dmax) were found as 21.7±8.4 (7.4-34) and 53.1±10.4 (25.4-64.4) Gy, respectively. V30 (%) and Dmean of heart were 22.3%±13.4% (3.9-47) and 21±5.7 (10.8-29.3) Gy, respectively. Dmax of medulla spinalis (MS) was 38.6± 1.3 (13.7-48) Gy. Grade 1-2 radiation pneumonitis (RP) developed in 4 (36.4%) and esophagitis in 2 (18.2%) patients. RP was found to be associated with MS and esophageal doses (p<0.05). Myelitis was diagnosed in 1 (9.1%) patient (MS Dmax: 29 Gy).
    CONCLUSION: HTT can be used as part of trimodality therapy for MPM patients with acceptable toxicities. MS and esophageal doses should be considered for radiation pneumonitis risk, and new dose constraints for these organs should be defined.
    Keywords:  Helical tomotherapy; hemithoracic radiotherapy; malignant pleural mesothelioma; trimodality therapy
    DOI:  https://doi.org/10.14744/nci.2023.53896
  5. Front Toxicol. 2023 ;5 1161995
    NF2 alteration in mesothelioma.
    Yoshitaka Sekido, Tatsuhiro Sato.
      The NF2 tumor suppressor gene is a frequent somatically mutated gene in mesothelioma, with 30%-40% mesotheliomas showing NF2 inactivation. NF2 encodes merlin, a member of the ezrin, radixin, and moesin (ERM) family of proteins that regulate cytoskeleton and cell signaling. Recent genome analysis revealed that NF2 alteration may be a late event in mesothelioma development, suggesting that NF2 mutation confers a more aggressive phenotype to mesothelioma cells and may not be directly caused by asbestos exposure. The Hippo tumor-suppressive and mTOR prooncogenic signaling pathways are crucial cell-signaling cascades regulated by merlin. Although the exact role and timing of NF2 inactivation in mesothelioma cells remain to be elucidated, targeting the NF2/merlin-Hippo pathway may be a new therapeutic strategy for patients with mesothelioma.
    Keywords:  Hippo pathway; NF2; genome; mesothelioma; tumor suppressor gene
    DOI:  https://doi.org/10.3389/ftox.2023.1161995
  6. Int J Mol Sci. 2023 Apr 24. pii: 7771. [Epub ahead of print]24(9):
    Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma.
    Marika A Franczak, Oliwia Krol, Gabriela Harasim, Agata Jedrzejewska, Nadia Zaffaroni, Carlotta Granchi, Filippo Minutolo, Amir Avan, Elisa Giovannetti, Ryszard T Smolenski, Godefridus J Peters.
      Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. The prognostic role of key effectors of glycolytic metabolism in MM prompted our studies on the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD+ metabolism, glycolysis and mitochondrial respiration. The antiproliferative activity of GLUT-1 (PGL13, PGL14) and LDH-A (NHI-1, NHI-2) inhibitors, alone and in combination, were tested with the sulforhodamine-B assay in peritoneal (MESO-II, STO) and pleural (NCI-H2052 and NCI-H28) MM and non-cancerous (HMEC-1) cells. Effects on energy metabolism were measured by both analysis of nucleotides using RP-HPLC and evaluation of glycolysis and respiration parameters using a Seahorse Analyzer system. All compounds reduced the growth of MM cells in the µmolar range. Interestingly, in H2052 cells, PGL14 decreased ATP concentration from 37 to 23 and NAD+ from 6.5 to 2.3 nmol/mg protein. NHI-2 reduced the ATP/ADP ratio by 76%. The metabolic effects of the inhibitors were stronger in pleural MM and in combination, while in HMEC-1 ATP reduction was 10% lower compared to that of the H2052 cells, and we observed a minor influence on mitochondrial respiration. To conclude, both inhibitors showed cytotoxicity in MM cells, associated with a decrease in ATP and NAD+, and were synergistic in the cells with the highest metabolic modulation. This underlines cellular energy metabolism as a potential target for combined treatments in selected cases of MM.
    Keywords:  anticancer treatment; cancer metabolism; chemoresistance; glucose transporter type 1; lactate dehydrogenase; malignant mesothelioma
    DOI:  https://doi.org/10.3390/ijms24097771
  7. Ann Diagn Pathol. 2023 Aug;pii: S1092-9134(23)00053-9. [Epub ahead of print]65 152155
    The clinicopathological significance of TOP2A expression in malignant peritoneal mesothelioma.
    Xuemei Du, Xinbao Li, Bingdong Zhang, Zechen Hao, Ying Gao, Xi Jiang, Zhiran Yang, Yizhi Chen.
       BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignant tumor with a high mortality rate and extremely poor prognosis. TOP2A expression is associated with cell proliferation and cell cycle progression. We aimed to demonstrate the expression profile of TOP2A in MPM and its correlation with clinicopathological features.
    METHODS: Clinicopathological information from 100 MPM cases was collected at Beijing Shijitan Hospital, Capital Medical University. Immunohistochemistry (IHC) was performed to evaluate TOP2A levels. The associations between TOP2A levels and clinicopathological features or prognosis were analyzed. Clinical follow-up data were reviewed to determine correlations among the pathological prognostic factors using the Kaplan-Meier estimator and univariate/multivariate Cox proportional hazards regression models.
    RESULTS: Among the 100 MPM patients, there were 48 males and 52 females, with a median age of 54 years (range: 24-72 years). The cutoff curve was used to find the boundary value of the TOP2A-positive rate. TOP2A positive rate ≥ 11.97 % accounted for 48 % in tumor tissue. The TOP2A-positive rate was not associated with sex, age, asbestos exposure, peritoneal carcinomatosis index (PCI) score, or completeness of cytoreduction (CC) score in MPM. Univariate analysis revealed survival-related pathological parameters, including asbestos exposure, CA125, histological type, PCI score, CC score, Ki-67 index, and TOP2A positive rate. Multivariate analysis identified that asbestos exposure history, PCI score, Ki-67 proliferation index and TOP2A positive rate in tissue are independent prognostic factors.
    CONCLUSIONS: High expression of TOP2A is linked to better prognosis of MPM.
    Keywords:  Ki-67; Malignant peritoneal mesothelioma; Survival; TOP2A
    DOI:  https://doi.org/10.1016/j.anndiagpath.2023.152155
  8. IUCrJ. 2023 Jul 01.
    The crystal structure of the killer fibre erionite from Tuzköy (Cappadocia, Turkey).
    Carlotta Giacobbe, Anna Moliterni, Dario Di Giuseppe, Daniele Malferrari, Jonathan P Wright, Michele Mattioli, Simona Ranieri, Cinzia Giannini, Laura Fornasini, Enrico Mugnaioli, Paolo Ballirano, Alessandro F Gualtieri.
      Erionite is a non-asbestos fibrous zeolite classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen and is considered today similar to or even more carcinogenic than the six regulated asbestos minerals. Exposure to fibrous erionite has been unequivocally linked to cases of malignant mesothelioma (MM) and this killer fibre is assumed to be directly responsible for more than 50% of all deaths in the population of the villages of Karain and Tuzköy in central Anatolia (Turkey). Erionite usually occurs in bundles of thin fibres and very rarely as single acicular or needle-like fibres. For this reason, a crystal structure of this fibre has not been attempted to date although an accurate characterization of its crystal structure is of paramount importance for our understanding of the toxicity and carcinogenicity. In this work, we report on a combined approach of microscopic (SEM, TEM, electron diffraction), spectroscopic (micro-Raman) and chemical techniques with synchrotron nano-single-crystal diffraction that allowed us to obtain the first reliable ab initio crystal structure of this killer zeolite. The refined structure showed regular T-O distances (in the range 1.61-1.65 Å) and extra-framework content in line with the chemical formula (K2.63Ca1.57Mg0.76Na0.13Ba0.01)[Si28.62Al7.35]O72·28.3H2O. The synchrotron nano-diffraction data combined with three-dimensional electron diffraction (3DED) allowed us to unequivocally rule out the presence of offretite. These results are of paramount importance for understanding the mechanisms by which erionite induces toxic damage and for confirming the physical similarities with asbestos fibres.
    Keywords:  ab initio structure solution; asbestos; erionite; mesothelioma; nano-diffraction
    DOI:  https://doi.org/10.1107/S2052252523003500
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