bims-mesote Biomed News
on Mesothelioma
Issue of 2022‒11‒13
eleven papers selected by
Laura Mannarino
Humanitas Research
  1. Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology.
  2. The Rocky Road from Preclinical Findings to Successful Targeted Therapy in Pleural Mesothelioma.
  3. Marital status as an independent prognostic factor for patients of malignant pleural mesothelioma.
  4. Immunostimulatory oncolytic activity of coxsackievirus A11 in human malignant pleural mesothelioma.
  5. Role of Prosaposin and Extracellular Sulfatase Sulf-1 Detection in Pleural Effusions as Diagnostic Biomarkers of Malignant Mesothelioma.
  6. Multifactorial Evaluation following Cytoreductive Surgery for Malignant Pleural Mesothelioma in Patients with High Symptom-Burden.
  7. The Association between the Histological Subtypes of Mesothelioma and Asbestos Exposure Characteristics.
  8. Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma.
  9. Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.
  10. Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers.
  11. SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma.
  1. Cancers (Basel). 2022 Oct 25. pii: 5216. [Epub ahead of print]14(21):
    Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology.
    Marcella Barbarino, Maria Bottaro, Laura Spagnoletti, Maria Margherita de Santi, Raffaella Guazzo, Chiara Defraia, Cosimo Custoza, Gabriella Serio, Francesco Iannelli, Matilde Pesetti, Raffaele Aiello, Diletta Rosati, Edoardo Zanfrini, Luca Luzzi, Cristiana Bellan, Antonio Giordano.
      The primary cilium (PC) is a sensory organelle present on the cell surface, modulating the activity of many pathways. Dysfunctions in the PC lead to different pathologic conditions including cancer. Hedgehog signaling (Hh) is regulated by PC and the loss of its control has been observed in many cancers, including mesothelioma. Malignant pleural mesothelioma (MPM) is a fatal cancer of the pleural membranes with poor therapeutic options. Recently, overexpression of the Hh transcriptional activator GL1 has been demonstrated to be associated with poor overall survival (OS) in MPM. However, unlike other cancers, the response to G-protein-coupled receptor smoothened (SMO)/Hh inhibitors is poor, mainly attributable to the lack of markers for patient stratification. For all these reasons, and in particular for the role of PC in the regulation of Hh, we investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with the activation of the Hh pathway, providing uncovered evidence of a PC-independent regulation of the Hh signaling in MPM. Our study contributes to the understanding MPM heterogeneity, thus helping to identify patients who might benefit from Hh inhibitors.
    Keywords:  GLI1; hedgehog signaling; mesothelioma; pleural; primary cilium
    DOI:  https://doi.org/10.3390/cancers14215216
  2. Int J Mol Sci. 2022 Nov 03. pii: 13422. [Epub ahead of print]23(21):
    The Rocky Road from Preclinical Findings to Successful Targeted Therapy in Pleural Mesothelioma.
    Juuso Paajanen, Raphael Bueno, Assunta De Rienzo.
      Pleural mesothelioma (PM) is a rare and aggressive disease that arises from the mesothelial cells lining the pleural cavity. Approximately 80% of PM patients have a history of asbestos exposure. The long latency period of 20-40 years from the time of asbestos exposure to diagnosis, suggests that multiple somatic genetic alterations are required for the tumorigenesis of PM. The genomic landscape of PM has been characterized by inter- and intratumor heterogeneity associated with the impairment of tumor suppressor genes such as CDKN2A, NF2, and BAP1. Current systemic therapies have shown only limited efficacy, and none is approved for patients with relapsed PM. Advances in understanding of the molecular landscape of PM has facilitated several biomarker-driven clinical trials but so far, no predictive biomarkers for targeted therapies are in clinical use. Recent advances in the PM genetics have provided optimism for successful molecular strategies in the future. Here, we summarize the molecular mechanism underlying PM pathogenesis and review potential therapeutic targets.
    Keywords:  gene therapy; genomics; pleural mesothelioma; targeted therapy
    DOI:  https://doi.org/10.3390/ijms232113422
  3. Front Med (Lausanne). 2022 ;9 955619
    Marital status as an independent prognostic factor for patients of malignant pleural mesothelioma.
    Shu Pan, Na Yan, Yuanyuan Zhao, Zhiwen Li.
      Objectives: The prognostic impact of marital status on malignant pleural mesothelioma (MPM) is not investigated. This paper probes into the relationship between the prognosis of MPM and marital status.Materials and methods: The Surveillance, Epidemiology, and End Results (SEER) database of American had been applied to choose eligible patients over the 2004-2015 periods. Moreover, cancer-specific survival (CSS) and overall survival (OS) of unmarried and married groups were compared.
    Results: A total of 3,997 patients in total had been identified, including 2,735 (68.43%) married patients. In comparison to unmarried patients, married ones tended to be younger, male, white, and received active treatment (surgery, chemotherapy, or radiotherapy). In addition, the 1, 3, and 5-year CSS rates were 44.40, 12.09, and 6.88% in married patients, while 35.75, 12.12, and 6.37% in unmarried group (p = 0.0014). At the same time, the 1, 3, and 5-year OS rates were 41.84, 10.56, and 5.91% in married patients, while 33.67, 10.44, and 4.93%, respectively, in the unmarried group (p < 0.0001). As revealed by the multivariate analysis results, the marital status was an independent favorable prognostic factor, in which the married groups showed better CSS [hazard ratio (HR): 0.870; 95% confidence interval (CI): 0.808-0.938; p < 0.001] as well as OS (HR: 0.871; 95% CI: 0.810-0.936; p < 0.001). According to the results of subgroup analysis, the CSS and OS survival of married groups were better than the unmarried groups in almost all the subgroups.
    Conclusion: Marital status is an independent favorable prognostic indicator of MPM. Poor prognosis in unmarried patients is likely to be related to insufficient treatments and socioeconomic and psychosocial factors.
    Keywords:  SEER; cancer specific survival; malignant pleural mesothelioma; marital status; overall survival; survival
    DOI:  https://doi.org/10.3389/fmed.2022.955619
  4. Cancer Sci. 2022 Nov 12.
    Immunostimulatory oncolytic activity of coxsackievirus A11 in human malignant pleural mesothelioma.
    Koji Okamura, Hiroyuki Inoue, Kentaro Tanaka, Yuki Ikematsu, Rie Furukawa, Keiichi Ota, Yasuto Yoneshima, Eiji Iwama, Isamu Okamoto.
      Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined, and showed no or minimal cytotoxicity towards human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule-1 (ICAM-1) expression tended to be more susceptible to CVA11-induced cytotoxicity, and a neutralizing antibody to ICAM-1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal-regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11-mediated cytotoxicity. Furthermore, CVA11 infection triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin-1β and damage-associated molecular patterns such as calreticulin, high-mobility group box-1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM-1 as a virus receptor as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM.
    Keywords:  Enterovirus; Immunogenic Cell Death; Intercellular Adhesion Molecule-1; Mesothelioma; Oncolytic Virotherapy
    DOI:  https://doi.org/10.1111/cas.15645
  5. Biomedicines. 2022 Nov 03. pii: 2803. [Epub ahead of print]10(11):
    Role of Prosaposin and Extracellular Sulfatase Sulf-1 Detection in Pleural Effusions as Diagnostic Biomarkers of Malignant Mesothelioma.
    Lorenzo Zallocco, Roberto Silvestri, Federica Ciregia, Alessandra Bonotti, Riccardo Marino, Rudy Foddis, Antonio Lucacchini, Laura Giusti, Maria Rosa Mazzoni.
      Malignant pleural mesothelioma is an aggressive malignancy with poor prognosis. Unilateral pleural effusion is frequently the initial clinical sign requiring therapeutic thoracentesis, which also offers a diagnostic opportunity. Detection of soluble biomarkers can support diagnosis, but few show good diagnostic accuracy. Here, we studied the expression levels and discriminative power of two putative biomarkers, prosaposin and extracellular sulfatase SULF-1, identified by proteomic and transcriptomic analysis, respectively. Pleural effusions from a total of 44 patients (23 with mesothelioma, 8 with lung cancer, and 13 with non-malignant disease) were analyzed for prosaposin and SULF-1 by enzyme-linked immunosorbent assay. Pleural effusions from mesothelioma patients had significantly higher levels of prosaposin and SULF-1 than those from non-malignant disease patients. Receiver-operating characteristic (ROC) analysis showed that both biomarkers have good discriminating power as pointed out by an AUC value of 0.853 (p = 0.0005) and 0.898 (p &lt; 0.0001) for prosaposin and SULF-1, respectively. Combining data ensued a model predicting improvement of the diagnostic performance (AUC = 0.916, p &lt; 0.0001). In contrast, prosaposin couldn't discriminate mesothelioma patients from lung cancer patients while ROC analysis of SULF-1 data produced an AUC value of 0.821 (p = 0.0077) but with low sensitivity. In conclusion, prosaposin and SULF-1 levels determined in pleural effusion may be promising biomarkers for differential diagnosis between mesothelioma and non-malignant pleural disease. Instead, more patients need to be enrolled before granting the possible usefulness of these soluble proteins in differentiating mesothelioma pleural effusions from those linked to lung cancer.
    Keywords:  biomarker; extracellular sulfatase Sulf-1; lung adenocarcinoma; mesothelioma; pleural effusion; prosaposin
    DOI:  https://doi.org/10.3390/biomedicines10112803
  6. J Clin Med. 2022 Oct 29. pii: 6418. [Epub ahead of print]11(21):
    Multifactorial Evaluation following Cytoreductive Surgery for Malignant Pleural Mesothelioma in Patients with High Symptom-Burden.
    Riccardo Tajè, Roberto Fiorito, Alexandro Patirelis, Valentina Marziali, Vincenzo Ambrogi.
      Mesothelioma has a scant prognosis and a great impact on symptoms and the quality of life. Pleurectomy/decortication and extrapleural pneumonectomy are the two cytoreductive surgical strategies, with different invasiveness, but achieving similar oncological results. Hereafter, the two surgical procedures effects on symptoms and the quality of life are compared in a high symptom-burden population. Between 2003 and 2017, 55 consecutive patients underwent pleurectomy/decortication (n = 26) or extrapleural pneumonectomy (n = 29), both followed by adjuvant chemo-radiotherapy. Cardio-pulmonary function, symptoms and the quality of life (Short-Form-36 and St.George's questionnaires) were evaluated pre- and 3-, 6-, 12- and 24-months postoperatively. Extrapleural pneumonectomy demonstrated lower pain at 12 months but a higher decrement of forced vital capacity at 24 months than pleurectomy/decortication. Both procedures revealed a 3-months improvement of many symptoms and the quality of life determinants. Improvement in physical, social and pain-related measured parameters lasted for a longer time-spawn in the extrapleural pneumonectomy group. No differences were found in chemotherapy compliance and survival between groups. Age-at-presentation (p = 0.02) and non-epitheliod histology (p = 0.10) were the only significant prognosticators. Surgery, despite poor survival results, improved symptoms and the quality of life in patients with mesothelioma with high symptom-burden at diagnosis. Therefore, extrapleural pneumonectomy demonstrated the most durable effects.
    Keywords:  extrapleural pneumonectomy; malignant pleural mesothelioma; pleural cancer; pleurectomy/decortication; quality of life; symptom control; symptom palliation
    DOI:  https://doi.org/10.3390/jcm11216418
  7. Int J Environ Res Public Health. 2022 Nov 05. pii: 14520. [Epub ahead of print]19(21):
    The Association between the Histological Subtypes of Mesothelioma and Asbestos Exposure Characteristics.
    Trudie Vorster, Julian Mthombeni, Jim teWaterNaude, James Ian Phillips.
      Asbestos mining operations have left South Africa with a legacy of asbestos contamination and asbestos-related diseases continue to be a problem. The large-scale mining of three types of asbestos presents a unique opportunity to study malignant mesothelioma of the pleura (mesothelioma) in South Africa. This study aimed to describe the demographics of deceased individuals diagnosed with mesothelioma and explore any associations between the histological morphology of mesothelioma and asbestos characteristics. We reviewed the records of all deceased miners and ex-miners from the Pathology Automation System (PATHAUT) database of the National Institute of Occupational Health (NIOH) that were histologically diagnosed with mesothelioma in the period from January 2006-December 2016 (11 years). The study population does not include all cases of mesothelioma in South Africa but rather those that reached the compensation system. Crocidolite asbestos fibres were identified in the majority of mesothelioma cases (n = 140; 53.4%). The epithelioid subtype was most commonly present in both occupational and environmental cases. Cases with the sarcomatous subtype were older at death and fewer female cases were diagnosed with this subtype. No relationship between mesothelioma subtype and asbestos type or asbestos burden or fibre size was established.
    Keywords:  PATHAUT; asbestos burden; asbestos type; mesothelioma; subtypes
    DOI:  https://doi.org/10.3390/ijerph192114520
  8. Carcinogenesis. 2022 Nov 10. pii: bgac089. [Epub ahead of print]
    Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma.
    Yuwaraj Kadariya, Eleonora Sementino, Ujjawal Shrestha, Greg Gorman, Jonathan M White, Eric A Ross, Margie L Clapper, Nouri Neamati, Mark Steven Miller, Joseph R Testa.
      Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model were tested in parallel. Asbestos-exposed Nf2  +/-;Cdkn2a  +/- mice treated with SC144, sulindac, or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.
    DOI:  https://doi.org/10.1093/carcin/bgac089
  9. Thorax. 2022 Nov 10. pii: thoraxjnl-2021-217862. [Epub ahead of print]
    Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.
    working group
      INTRODUCTION: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy.METHOD: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE).
    RESULT: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE.
    CONCLUSION: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.
    Keywords:  asbestos induced lung disease; lung cancer; mesothelioma
    DOI:  https://doi.org/10.1136/thorax-2021-217862
  10. Int J Mol Sci. 2022 Nov 07. pii: 13628. [Epub ahead of print]23(21):
    Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers.
    Sergio Crovella, Ronald Rodrigues Moura, Lucas Brandão, Francesca Vita, Manuela Schneider, Fabrizio Zanconati, Luigi Finotto, Paola Zacchi, Giuliano Zabucchi, Violetta Borelli.
      The variant enrichment analysis (VEA), a recently developed bioinformatic workflow, has been shown to be a valuable tool for whole-exome sequencing data analysis, allowing finding differences between the number of genetic variants in a given pathway compared to a reference dataset. In a previous study, using VEA, we identified different pathway signatures associated with the development of pulmonary toxicities in mesothelioma patients treated with radical hemithoracic radiation therapy. Here, we used VEA to discover novel pathways altered in individuals exposed to asbestos who developed or not asbestos-related diseases (lung cancer or mesothelioma). A population-based autopsy study was designed in which asbestos exposure was evaluated and quantitated by investigating objective signs of exposure. We selected patients with similar exposure to asbestos. Formalin-fixed paraffin-embedded (FFPE) tissues were used as a source of DNA and whole-exome sequencing analysis was performed, running VEA to identify potentially disrupted pathways in individuals who developed thoracic cancers induced by asbestos exposure. By using VEA analysis, we confirmed the involvement of pathways considered as the main culprits for asbestos-induced carcinogenesis: oxidative stress and chromosome instability. Furthermore, we identified protective genetic assets preserving genome stability and susceptibility assets predisposing to a worst outcome.
    Keywords:  FFPE (fixed in formalin and embedded in paraffin); asbestos; lung cancer; mesothelioma; variant enrichment analysis (VEA); whole exome
    DOI:  https://doi.org/10.3390/ijms232113628
  11. Cell Death Discov. 2022 Nov 05. 8(1): 446
    SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma.
    Koya Suzuki, Masaki Tange, Ryota Yamagishi, Hiroyuki Hanada, Satomi Mukai, Tatsuhiro Sato, Takeshi Tanaka, Tomohiro Akashi, Kenji Kadomatsu, Tohru Maeda, Takashi Miida, Ichiro Takeuchi, Hiroshi Murakami, Yoshitaka Sekido, Yuko Murakami-Tonami.
      Many genes responsible for Malignant mesothelioma (MM) have been identified as tumor suppressor genes and it is difficult to target these genes directly at a molecular level. We searched for the gene which showed synthetic lethal phenotype with LATS2, one of the MM causative genes and one of the kinases in the Hippo pathway. Here we showed that knockdown of SMG6 results in synthetic lethality in LATS2-inactivated cells. We found that this synthetic lethality required the nuclear translocation of YAP1 and TAZ. Both are downstream factors of the Hippo pathway. We also demonstrated that this synthetic lethality did not require SMG6 in nonsense-mediated mRNA decay (NMD) but in regulating telomerase reverse transcriptase (TERT) activity. In addition, the RNA-dependent DNA polymerase (RdDP) activity of TERT was required for this synthetic lethal phenotype. We confirmed the inhibitory effects of LATS2 and SMG6 on cell proliferation in vivo. The result suggests an interaction between the Hippo and TERT signaling pathways. We also propose that SMG6 and TERT are novel molecular target candidates for LATS2-inactivated cancers such as MM.
    DOI:  https://doi.org/10.1038/s41420-022-01232-w
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