scholarly journals Metabolic rewiring and redox alterations in malignant pleural mesothelioma

2019 ◽  
Vol 122 (1) ◽  
pp. 52-61 ◽  
Author(s):  
Loredana Urso ◽  
Ilaria Cavallari ◽  
Evgeniya Sharova ◽  
Francesco Ciccarese ◽  
Giulia Pasello ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Malignant Pleural Mesothelioma ◽  
Tumour Progression ◽  
Mesothelial Cells ◽  
Polyamine Metabolism ◽  
Aetiological Factor ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
Control Of Gene Expression ◽  
Dismal Prognosis

AbstractMalignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in 18F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.

scholarly journals Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma

2018 ◽  
Vol 51 (5) ◽  
pp. 1701610 ◽  
Author(s):  
Takahiko Otsuki ◽  
Taku Nakashima ◽  
Hironobu Hamada ◽  
Yusuke Takayama ◽  
Shin Akita ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Molecular Target ◽  
Aminopeptidase N ◽  
Pleural Mesothelioma ◽  
Tumour Angiogenesis ◽  
Potential Therapeutic Target

Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.

scholarly journals Metformin Induces Apoptosis and Inhibits Notch1 in Malignant Pleural Mesothelioma Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Marika Rossini ◽  
Fernanda Martini ◽  
Elena Torreggiani ◽  
Francesca Fortini ◽  
Giorgio Aquila ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Notch Pathway ◽  
Cell Communication ◽  
Mesothelial Cells ◽  
Pleural Mesothelioma ◽  
Proliferative Effect ◽  
Pleural Mesothelial Cells ◽  
Different Types ◽  
Line Drug

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related cancer arising from the mesothelial cells lining the pleural cavity. MPM is characterized by a silent clinical progression and a highly resistance to conventional chemo/radio-therapies. MPM patients die in a few months/years from diagnosis. Notch signaling is a well-conserved cell communication system, which regulates many biological processes. In humans, the dysregulation of Notch pathway potentially contributes to cancer onset/progression, including MPM. Metformin is the first-line drug used to treat type 2 diabetes mellitus. Metformin is proven to be an effective antitumor drug in preclinical models of different types of cancer. To date, clinical efficacy is being studied in many clinical trials. In this study, the anti-proliferative effect of metformin on MPM cells and the putative involvement of Notch1 as a mediator of metformin activities, were investigated. MPM cells showed high levels of Notch1 activation compared to normal pleural mesothelial cells. Furthermore, metformin treatment hampered MPM cell proliferation and enhanced the apoptotic process, accompanied by decreased Notch1 activation.

scholarly journals Evaluation of imaging techniques for the assessment of tumour progression in an orthotopic rat model of malignant pleural mesothelioma†

2014 ◽  
Vol 47 (1) ◽  
pp. e34-e41 ◽  
Author(s):  
Mayura Meerang ◽  
Andreas Boss ◽  
David Kenkel ◽  
Angela Broggini-Tenzer ◽  
Karima Bérard ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Rat Model ◽  
Tumour Progression ◽  
Imaging Techniques ◽  
Pleural Mesothelioma

scholarly journals Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM)

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 7
Author(s):  
Moshe Lapidot ◽  
Abigail E. Case ◽  
Dalia Larios ◽  
Helen I. Gandler ◽  
Chengcheng Meng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcription Factor ◽  
Cell Growth ◽  
Malignant Pleural Mesothelioma ◽  
Cell Cycle Progression ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
P53 Response

Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.

scholarly journals Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM)

2021 ◽  
Author(s):  
Moshe Lapidot ◽  
Abigail E. Case ◽  
Ellen L. Weisberg ◽  
Chengcheng Meng ◽  
Sarah R. Walker ◽  
...  
Keyword(s):  
Cell Growth ◽  
Malignant Pleural Mesothelioma ◽  
Essential Role ◽  
Strand Break ◽  
Pleural Mesothelioma ◽  
Replication Checkpoint ◽  
Regulatory Pathways ◽  
Dismal Prognosis

Abstract Background Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM. Methods KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways. Results Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth. Conclusions The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.

scholarly journals BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma

2020 ◽  
Author(s):  
Y Ishii ◽  
KK Kolluri ◽  
A Pennycuick ◽  
E Nigro ◽  
D Alrifai ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Regulation Of Gene Expression ◽  
Inverse Correlation ◽  
Death Receptors ◽  
Tumour Suppressor Gene ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
Incurable Cancer ◽  
Trail Receptors ◽  
Frequent Event

AbstractMalignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the lungs with few treatment options. We recently reported loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptors 4 (DR4) and 5 (DR5). Using tissue microarray (TMAs) of tumour samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptors. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wild-type BAP1, but not catalytically-inactive mutant BAP1, reduced promoter activities of DR4 and DR5, suggesting deubiquinase activity plays an important role in the regulation of gene expression. Co-IP studies demonstrated direct binding of BAP1 and the transcription factor Ying Yang 1 (YY1) and ChIP assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Notably, shRNA knockdown of YY1 also increased DR4 and DR5 expression, and sensitivity to TRAIL. These results demonstrate that BAP1 and YY1 together negatively regulate transcriptional activity of TRAIL receptors. BAP1 and YY1 may both therefore be strong therapeutic targets to enhance the efficacy of TRAIL-induced apoptosis.Statement of significanceWe describe how the most-frequently mutated tumour suppressor gene in mesothelioma regulates the response to TNF-related apoptosis-inducing ligand (TRAIL). These findings will accelerate a biomarker-driven cancer therapy.

scholarly journals Intrapleural hyperthermic chemotherapy induces pro-immunogenic e-selectin expression in the vasculature of malignant pleural mesothelioma

2021 ◽  
Vol 108 (Supplement_4) ◽  
Author(s):  
Y Hao ◽  
L -E Chriqui ◽  
C Gattlen ◽  
M Gonzalez ◽  
T Krueger ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Line ◽  
Malignant Pleural Mesothelioma ◽  
Adhesion Molecule ◽  
Connexin 43 ◽  
Expression Patterns ◽  
Pleural Mesothelioma ◽  
Hyperthermic Chemotherapy ◽  
Dismal Prognosis ◽  
The Impact

Abstract Objective Malignant pleural mesothelioma (MPM) is a deadly disease with dismal prognosis. Prior studies combining surgery with intrapleural hyperthermic chemotherapy (IPHC) have shown improved survivals in selected patients with MPM. However, the mechanisms by which IPHC acts on MPM and its microenvironment remains unknown. Here we focus on tumor endothelial adhesion molecule expression patterns. Methods First, we determined the impact of IPHC on MPM tumor and vascular compartments in vitro using a novel bioincubater for hyperthermic cell culture. The cytotoxicity of normo (37 °C) / hyperthermic (42 °C for 60 minutes) cisplatin/carboplatin therapies were evaluated on four MPM (MSTO211H, H-Meso, AE17 and AB12) and one endothelial (EC-RF24) cell lines at a minimum of 24 hours using a presto-blue assay. Second, we treated endothelial cells with IPHC (60 min, 42 °C at optimized cytotoxic concentrations) and determined its impact on pro-immunogenic adhesion molecule (E-selectin, VE-cadherin, VCAM and Connexin-43) expression at 24 hours by Western blot. Results Tumor and endothelial cell viability decreased with increasing doses of both chemotherapeutics but was not affected by hyperthermia (IC50 with or without hyperthermia of each cell line at 24 hours reported in Figure 1A). Interestingly, endothelial cell line IC50 was much higher than that of MPM tumor cells for both chemotherapeutics (Figure 1A). Pro-immunogenic adhesion molecule E-Selectin was increased at 24 hours by IPHC with both chemotherapeutics while VE-Cadherin, VCAM and Connexin-43 were not affected (Figure 1B). Conclusion Hyperthermia adds no cytotoxicity to intrapleural chemotherapy. However, IPHC favors pro-immunogenic endothelial E-selectin expression. The latter could help induce patient immunity against their MPM and improve survival. Confirmation of these findings in vivo is mandatory.

Ovarian metastasis from malignant pleural mesothelioma

2020 ◽  
Vol 106 (6) ◽  
pp. NP49-NP51
Author(s):  
Giuseppe Naldi ◽  
Serenella Bergomi ◽  
Paolo Visca ◽  
Fabiana Letizia Cecere
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Distant Metastases ◽  
Ovarian Metastasis ◽  
Whole Body ◽  
Pleural Mesothelioma ◽  
Ovarian Metastases ◽  
Dismal Prognosis ◽  
Positron Emission ◽  
Improve Patient Management ◽  
Improve Patient

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive disease of the pleura with a dismal prognosis. Distant metastases most commonly occur in the liver, spleen, and thyroid gland. To our knowledge, ovarian metastases have never been described. Case description: We describe a case of a woman with recurrent malignant pleural mesothelioma presenting a single ovarian metastasis, surgically resected. Conclusions: This case report highlights the importance of using a complete staging protocol in patients with MPM to improve patient management. A whole-body computed tomography (CT) scan with contrast enhancement and possibly positron emission tomography–CT should be performed to identify any distant metastases before deciding on treatment strategy.

Malignant Mesothelioma: Has Anything Changed?

2019 ◽  
Vol 40 (03) ◽  
pp. 347-360 ◽  
Author(s):  
Roger Y. Kim ◽  
Daniel H. Sterman ◽  
Andrew R. Haas
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Multimodal Therapy ◽  
Asbestos Exposure ◽  
Treatment Options ◽  
Standard Of Care ◽  
Turn Of The Century ◽  
Clinical Approach ◽  
Pleural Mesothelioma ◽  
Dismal Prognosis ◽  
Near Future

AbstractMalignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma.

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