bims-mesote 2022-12-18 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–12–18
eight papers selected by
Laura Mannarino, Humanitas Research

Identification of glycolysis genes signature for predicting prognosis in malignant pleural mesothelioma by bioinformatics and machine learning.
CDK4/6 Inhibition Enhances the Efficacy of Standard Chemotherapy Treatment in Malignant Pleural Mesothelioma Cells.
Potential Roles of Exosomes in the Development and Detection of Malignant Mesothelioma: An Update.
Disease Latency according to Asbestos Exposure Characteristics among Malignant Mesothelioma and Asbestos-Related Lung Cancer Cases in South Korea.
Multimodal therapy of epithelioid pleural mesothelioma: improved survival by changing the surgical treatment approach.
Corrigendum: CDKN2A determines mesothelioma cell fate to EZH2 inhibition.
Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology.
Diverse and divergent functions of IL-32β and IL-32γ isoforms in the regulation of malignant pleural mesothelioma cell growth and the production of VEGF-A and CXCL8.

Front Endocrinol (Lausanne). 2022 ;13 1056152

Identification of glycolysis genes signature for predicting prognosis in malignant pleural mesothelioma by bioinformatics and machine learning.

Yingqi Xiao, Wei Huang, Li Zhang, Hongwei Wang.

   Background: Glycolysis-related genes as prognostic markers in malignant pleural mesothelioma (MPM) is still unclear. We hope to explore the relationship between glycolytic pathway genes and MPM prognosis by constructing prognostic risk models through bioinformatics and machine learning.
Methods: The authors screened the dataset GSE51024 from the GEO database for Gene set enrichment analysis (GSEA), and performed differentially expressed genes (DEGs) of glycolytic pathway gene sets. Then, Cox regression analysis was used to identify prognosis-associated glycolytic genes and establish a risk model. Further, the validity of the risk model was evaluated using the dataset GSE67487 in GEO database, and finally, a specimen classification model was constructed by support vector machine (SVM) and random forest (RF) to further screen prognostic genes.
Results: By DEGs, five glycolysis-related pathway gene sets (17 glycolytic genes) were identified to be highly expressed in MPM tumor tissues. Also 11 genes associated with MPM prognosis were identified in TCGA-MPM patients, and 6 (COL5A1, ALDH2, KIF20A, ADH1B, SDC1, VCAN) of them were included by Multi-factor COX analysis to construct a prognostic risk model for MPM patients, with Area under the ROC curve (AUC) was 0.830. Further, dataset GSE67487 also confirmed the validity of the risk model, with a significant difference in overall survival (OS) between the low-risk and high-risk groups (P < 0.05). The final machine learning screened the five prognostic genes with the highest risk of MPM, in order of importance, were ALDH2, KIF20A, COL5A1, ADH1B and SDC1.
Conclusions: A risk model based on six glycolytic genes (ALDH2, KIF20A, COL5A1, ADH1B, SDC1, VCAN) can effectively predict the prognosis of MPM patients.

Keywords:  gene set enrichment analysis (GSEA); glycolysis; machine learning; malignant pleural mesothelioma (MPM); prognostic risk model

DOI:  https://doi.org/10.3389/fendo.2022.1056152
Cancers (Basel). 2022 Nov 30. pii: 5925. [Epub ahead of print]14(23):

CDK4/6 Inhibition Enhances the Efficacy of Standard Chemotherapy Treatment in Malignant Pleural Mesothelioma Cells.

Rita Terenziani, Maricla Galetti, Silvia La Monica, Claudia Fumarola, Silvia Zoppi, Roberta Alfieri, Graziana Digiacomo, Andrea Cavazzoni, Delia Cavallo, Massimo Corradi, Marcello Tiseo, Pier Giorgio Petronini, Mara Bonelli.

   BACKGROUND: The loss of the CDKN2A/ARF (cyclin-dependent kinase inhibitor 2A/alternative reading frame) gene is the most common alteration in malignant pleural mesothelioma (MPM), with an incidence of about 70%, thus representing a novel target for mesothelioma treatment. In the present study, we evaluated the antitumor potential of combining the standard chemotherapy regimen used for unresectable MPM with the CDK4/6 (cyclin-dependent kinase 4 or 6) inhibitor abemaciclib.
METHODS: Cell viability, cell death, senescence, and autophagy induction were evaluated in two MPM cell lines and in a primary MPM cell culture.
RESULTS: The simultaneous treatment of abemaciclib with cisplatin and pemetrexed showed a greater antiproliferative effect than chemotherapy alone, both in MPM cell lines and in primary cells. This combined treatment induced cellular senescence or autophagic cell death, depending on the cell type. More in detail, the induction of cellular senescence was related to the increased expression of p21, whereas autophagy induction was due to the impairment of the AKT/mTOR signaling. Notably, the effect of the combination was irreversible and no resumption in tumor cell proliferation was observed after drug withdrawal.
CONCLUSION: Our results demonstrated the therapeutic potential of CDK4/6 inhibitors in combination with chemotherapy for the treatment of MPM and are consistent with the recent positive results in the MiST2 arm in abemaciclib-treated patients.

Keywords:  CDK4/6 inhibitors; abemaciclib; chemotherapy; malignant pleural mesothelioma; senescence

DOI:  https://doi.org/10.3390/cancers14235925
Int J Mol Sci. 2022 Dec 06. pii: 15438. [Epub ahead of print]23(23):

Potential Roles of Exosomes in the Development and Detection of Malignant Mesothelioma: An Update.

Phillip Munson, Arti Shukla.

  Malignant mesothelioma (MM) is a devastating cancer of mesothelial cells, caused by asbestos exposure. Limited knowledge regarding the detection of asbestos exposure and the early diagnosis of MM, as well as a lack of successful treatment options for this deadly cancer, project an immediate need to understand the mechanism(s) of MM development. With the recent discovery of nano-vesicles, namely exosomes, and their enormous potential to contain signature molecules representative of different diseases, as well as to communicate with distant targets, we were encouraged to explore their role(s) in MM biology. In this review, we summarize what we know so far about exosomes and MM based on our own studies and on published literature from other groups in the field. We expect that the information contained in this review will help advance the field of MM forward by revealing the mechanisms of MM development and survival. Based on this knowledge, future therapeutic strategies for MM can potentially be developed. We also hope that the outcome of our studies presented here may help in the detection of MM.

Keywords:  asbestos; exosomes; malignant mesothelioma

DOI:  https://doi.org/10.3390/ijms232315438
Int J Environ Res Public Health. 2022 Nov 29. pii: 15934. [Epub ahead of print]19(23):

Disease Latency according to Asbestos Exposure Characteristics among Malignant Mesothelioma and Asbestos-Related Lung Cancer Cases in South Korea.

Da-An Huh, Woo-Ri Chae, Yun-Hee Choi, Min-Sung Kang, Yong-Jin Lee, Kyong-Whan Moon.

  Korea was one of the major consumers of asbestos in the late 1900s, and asbestos-related disease patients have been reported continuously to date, owing to long disease latency. Several studies have been conducted to predict the future incidence of malignant mesothelioma and lung cancer in Korea, but little is understood about the latency time. Therefore, the aim of this study is to estimate the latency period of malignant mesothelioma and asbestos-related lung cancer in Korea and its determinants. We obtained information from the Environmental Health Centers for Asbestos in Korea on the history of asbestos exposure and demographic characteristics of 1933 patients with malignant mesothelioma and asbestos-related lung cancer. In our study, the latency periods for malignant mesothelioma and lung cancer were 33.7 and 40.1 years, respectively. Regardless of the disease type, those with a history of exposure related to the production of asbestos-containing products or asbestos factories had the shortest latency period. In addition, we observed that those who worked in or lived near asbestos mines tended to have a relatively long disease latency. Smoking was associated with shorter latency, but no linear relationship between the lifetime smoking amount (expressed in pack years) and latent time was observed. In addition, the age of initial exposure showed a negative linear association with the latency period for mesothelioma and lung cancer.

Keywords:  asbestos; latency period; lung cancer; malignant mesothelioma

DOI:  https://doi.org/10.3390/ijerph192315934
Transl Lung Cancer Res. 2022 Nov;11(11): 2230-2242

Multimodal therapy of epithelioid pleural mesothelioma: improved survival by changing the surgical treatment approach.

Laura V Klotz, Hans Hoffmann, Rajiv Shah, Florian Eichhorn, Christiane Gruenewald, Elena L Bulut, Raffaella Griffo, Thomas Muley, Petros Christopoulos, Philip Baum, Peter Huber, Seyer Safi, Marc Kriegsmann, Michael Thomas, Helge Bischoff, Hauke Winter, Martin E Eichhorn.

   Background: The exact role and type of surgery for malignant pleural mesothelioma (MPM) remains controversial. This study aimed at analyzing a 20-year single center perioperative experience in MPM surgery at our high-volume thoracic surgery center and comparing the overall survival after trimodal extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication combined with hyperthermic intrathoracic chemoperfusion (EPD/HITOC) and adjuvant chemotherapy with that after chemotherapy (CTx) alone.
Methods: Patients with epithelioid MPM treated with neoadjuvant chemotherapy, EPP and adjuvant radiotherapy within a trimodal concept or EPD/HITOC in combination with adjuvant chemotherapy between 2001 and 2018 were included in this retrospective analysis. Surgical cohorts were compared to patients treated with standard chemotherapy.
Results: Overall, 182 patients (69 EPP, 57 EPD/HITOC, 56 CTx) were analyzed. Due to occupational exposure to asbestos for most of the patients, 154 patients (84.6%) were male. The patients in the surgical cohorts were significantly younger than those in the CTx cohort. There was no significant difference between the proportion of patient age and side. The median overall survival of the EPD/HITOC cohort with 38.1 months was significantly longer than that of the EPP and CTx cohorts (24.0 and 15.8 months). Better survival was significantly associated with an ECOG 0 performance status, age below 70 years, and negative lymph node status. In the multivariate analysis, EPD/HITOC was significantly associated with improved overall survival. Perioperative morbidity was lower in the EPD/HITOC group than in the EPP cohort.
Conclusions: EPD/HITOC is feasible and safe for localized epithelioid pleural mesothelioma. Changing the surgical approach to a less radical lung-sparing technique may improve overall survival compared to trimodal EPP.

Keywords:  Pleural mesothelioma; chemoperfusion; cytoreductive surgery; decortication; extrapleural pneumonectomy

DOI:  https://doi.org/10.21037/tlcr-22-199
Front Oncol. 2022 ;12 1081632

Corrigendum: CDKN2A determines mesothelioma cell fate to EZH2 inhibition.

Giulia Pinton, Zhuo Wang, Cecilia Balzano, Sara Missaglia, Daniela Tavian, Renzo Boldorini, Dean A Fennell, Martin Griffin, Laura Moro.

  [This corrects the article DOI: 10.3389/fonc.2021.678447.].

Keywords:  CDKN2A/p16ink4a; EZH2 inhibitor; TG2; malignant pleural mesothelioma; multicellular spheroids

DOI:  https://doi.org/10.3389/fonc.2022.1081632
J Transl Med. 2022 Dec 13. 20(1): 593

Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology.

Tomer Meirson, Valerio Nardone, Francesca Pentimalli, Gal Markel, David Bomze, Maria D'Apolito, Pierpaolo Correale, Antonio Giordano, Luigi Pirtoli, Camillo Porta, Steven G Gray, Luciano Mutti.

In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting "pleural mesothelioma" as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.

DOI: https://doi.org/10.1186/s12967-022-03744-6
Cell Immunol. 2022 Nov 30. pii: S0008-8749(22)00177-0. [Epub ahead of print]383 104652

Diverse and divergent functions of IL-32β and IL-32γ isoforms in the regulation of malignant pleural mesothelioma cell growth and the production of VEGF-A and CXCL8.

Muneo Numasaki, Koyu Ito, Kiyoshi Takagi, Kengo Nagashima, Hirotsugu Notsuda, Hirokazu Ogino, Rika Ando, Yoshihisa Tomioka, Takashi Suzuki, Yoshinori Okada, Yasuhiko Nishioka, Michiaki Unno.

  In this study, we sought to elucidate the roles of the interleukin (IL)-32β and IL-32γ in mesothelioma cell growth, and vascular endothelial growth factor (VEGF)-A and C-X-C motif chemokine ligand 8 (CXCL8) expression. IL-32 elicited a growth-promoting effect against one of the six mesotheliomas lines and exerted diverse regulatory functions in VEGF-A and CXCL8 secretion from mesotheliomas stimulated with or without IL-17A. Retroviral-mediated transduction of mesothelioma lines with IL-32γ resulted in enhanced IL-32β expression, which facilitated or suppressed the in vitro growth, and VEGF-A and CXCL8 expression. Overexpressed IL-32β-augmented growth and VEGF-A and CXCL8 production were mainly mediated through the phosphatidylinositol-3 kinase (PI3K) signaling pathway. On the other hand, overexpressed IL-32β-deceased growth was mediated through mitogen-activated protein kinase (MAPK) pathway. NCI-H2373IL-32γ tumors grew faster than NCI-H2373Neo tumors in a xenograft model, which was associated with increased vascularity. These findings indicate that IL-32 are involved in the regulation of growth and angiogenic factor production in mesotheliomas.

Keywords:  CXCL8; IL-17A; IL-32; Malignant pleural mesothelioma; VEGF-A

DOI:  https://doi.org/10.1016/j.cellimm.2022.104652