bims-mesote 2023-02-26 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023–02–26
six papers selected by
Laura Mannarino, Humanitas Research

Small RNA-Seq Transcriptome Profiling of Mesothelial and Mesothelioma Cell Lines Revealed microRNA Dysregulation after Exposure to Asbestos-like Fibers.
Asbestos Consumption and Malignant Mesothelioma Mortality Trends in the Major User Countries.
Highlighting the immunohistochemical differences of malignant mesothelioma subtypes via case presentations.
Malignant Pleural Mesothelioma: Preliminary Toxicity Results of Adjuvant Radiotherapy Hypofractionation in a Prospective Trial (MESO-RT).
Identification of a derivative of the alkaloid emetine as an inhibitor of the YAP-TEAD interaction and its potential as an anticancer agent.
Defining and targeting tumor-associated macrophages in malignant mesothelioma.

Biomedicines. 2023 Feb 13. pii: 538. [Epub ahead of print]11(2):

Small RNA-Seq Transcriptome Profiling of Mesothelial and Mesothelioma Cell Lines Revealed microRNA Dysregulation after Exposure to Asbestos-like Fibers.

Veronica Filetti, Claudia Lombardo, Carla Loreto, George Dounias, Massimo Bracci, Serena Matera, Lucia Rapisarda, Venerando Rapisarda, Caterina Ledda, Ermanno Vitale.

  Environmental exposure to fibers of respirable size has been identified as a risk for public health. Experimental evidence has revealed that a variety of fibers, including fluoro-edenite, can develop chronic respiratory diseases and elicit carcinogenic effects in humans. Fluoro-edenite (FE) is a silicate mineral first found in Biancavilla (Sicily, Italy) in 1997. Environmental exposure to its fibers has been correlated with a cluster of malignant pleural mesotheliomas. This neoplasm represents a public health problem due to its long latency and to its aggression not alerted by specific symptoms. Having several biomarkers providing us with data on the health state of those exposed to FE fibers or allowing an early diagnosis on malignant pleural mesothelioma, still asymptomatic patients, would be a remarkable goal. To these purposes, we reported the miRNA transcriptome in human normal mesothelial cell line (MeT-5A) and in the human malignant mesothelioma cell line (JU77) exposed and not exposed to FE fibers. The results showed a difference in the number of deregulated miRNAs between tumor and nontumor samples both exposed and not exposed to FE fibers. As a matter of fact, the effect of exposure to FE fibers is more evident in the expression of miRNA in the tumor samples than in the nontumor samples. In the present paper, several pathways involved in the pathogenesis of malignant pleural mesothelioma have been analyzed. We especially noticed the involvement of pathways that have important functions in inflammatory processes, angiogenesis, apoptosis, and necrosis. Besides this amount of data, further studies will be designed for the selection of the most significant miRNAs to test and validate their diagnostic potential, alone or in combination with other protein biomarkers, in high-risk individuals' liquid biopsy to have a noninvasive tool of diagnosis for this neoplasm.

Keywords:  asbestos-like fibers; biomarkers; fluoro-edenite; malignant mesothelioma; small RNA-Seq transcriptome profiling

DOI:  https://doi.org/10.3390/biomedicines11020538
Ann Glob Health. 2023 ;89(1): 11

Asbestos Consumption and Malignant Mesothelioma Mortality Trends in the Major User Countries.

Claudio Gariazzo, Antonio Gasparrini, Alessandro Marinaccio.

   Background: The causal association between mesothelioma and asbestos exposure is conclusive, and many studies have proved that the trend in asbestos use is a strong predictor of the pattern in mesothelioma cases with an adequate latency time (generally around 30-40 years or more). Recently, a novel approach for predicting malignant pleural mesothelioma, based on asbestos consumption trend and using distributed non-linear models, has been applied.
Objectives: The purpose of this study is to analyse trends in asbestos consumption and malignant mesothelioma mortality in the major asbestos-user countries. Furthermore, we applied distributed non-linear models to estimate and compare epidemiological relationships between asbestos consumption and mesothelioma mortality across these countries.
Methods: The study involves major asbestos-user countries in which historical asbestos consumption and mesothelioma mortality data are available. Data on asbestos consumption were derived from worldwide asbestos supply and mesothelioma mortality data from World Health Organization (WHO) mortality archives. A quasi-Poisson generalized linear model was used to model past asbestos exposure and male mesothelioma mortality rates in each country. Exposure-response associations have been modelled using distributed lag non-linear models.
Findings and conclusions: According to the criteria defined above, we selected 18 countries with raw asbestos cumulative consumptions higher than two million tons in the period 1933-2012. Overall, a clear linear relationship can be observed between total consumption and total deaths for mesothelioma. Country-specific exposure, lag and age-response relationships were identified and common functions extracted by a meta-analysis procedure. Non-linear models appear suitable and flexible tools for investigating the association between mesothelioma mortality and asbestos consumption. There is a need to improve the global epidemiological surveillance of asbestos-related diseases, particularly mesothelioma mortality, and the absence of reliable data for some major asbestos-user countries is a real concern. A reliable assessment of mesothelioma mortality is a fundamental step towards increasing the awareness of related risks and the need of an international ban on asbestos.

Keywords:  asbestos; distributed non-linear models; international ban; mesothelioma; mortality

DOI:  https://doi.org/10.5334/aogh.4012
Thorac Cancer. 2023 Feb 20.

Highlighting the immunohistochemical differences of malignant mesothelioma subtypes via case presentations.

Anita Sejben, Tamás Pancsa, László Tiszlavicz, József Furák, Dóra Paróczai, Tamás Zombori.

  Malignant mesothelioma (MM) is a rare tumor of mesothelial cells, with an increasing incidence both in developed and developing countries. MM has three major histological subtypes, in order of frequency, according to the World Health Organization (WHO) Classification of 2021: epithelioid, biphasic, and sarcomatoid MM. Distinction may be a challenging task for the pathologist, due to the unspecific morphology. Here, we present two cases of diffuse MM subtypes to emphasize the immunohistochemical (IHC) differences, and to facilitate diagnostic difficulties. In our first case of epithelioid mesothelioma, the neoplastic cells showed cytokeratin 5/6 (CK5/6), calretinin, and Wilms-tumor-1 (WT1) expression, while remaining negative with thyroid transcription factor-1 (TTF-1). BRCA1 associated protein-1 (BAP1) negativity was seen in the neoplastic cells' nucleus, reflecting loss of the tumor suppressor gene. In the second case of biphasic mesothelioma, expression of epithelial membrane antigen (EMA), CKAE1/AE3, and mesothelin was observed, while WT1, BerEP4, CD141, TTF1, p63, CD31, calretinin, and BAP1 expressions were not detected. Due to the absence of specific histological features, the differentiation between MM subtypes could be a challenging task. In routine diagnostic work, IHC may be the proper method in distinction. According to our results and literature data, CK5/6, mesothelin, calretinin, and Ki-67 should be applied in subclassification.

Keywords:  asbestos; epithelioid; immunohistochemistry; malignant mesothelioma; sarcomatoid malignant mesothelioma

DOI:  https://doi.org/10.1111/1759-7714.14827
Cancers (Basel). 2023 Feb 07. pii: 1057. [Epub ahead of print]15(4):

Malignant Pleural Mesothelioma: Preliminary Toxicity Results of Adjuvant Radiotherapy Hypofractionation in a Prospective Trial (MESO-RT).

Elisabetta Parisi, Donatella Arpa, Giulia Ghigi, Lucia Fabbri, Flavia Foca, Luca Tontini, Elisa Neri, Martina Pieri, Simona Cima, Marco Angelo Burgio, Maria Luisa Belli, Luca Luzzi, Antonino Romeo.

  Malignant Pleural Mesothelioma (MPM) is a rare malignancy with an overall poor prognosis. The standard therapeutic strategy in early-stage disease is trimodality therapy. In this publication, we report the preliminary toxicity results of the first 20 patients treated with accelerated hypofractionated radiotherapy. Between July 2017 to June 2019, 20 MPM patients were enrolled and treated with accelerated hypofractionated radiotherapy using helical tomotherapy and intensity-modulated arc therapy. The prescription dose was 30 Gy in five daily fractions, while an inhomogeneous dose escalation to 40 Gy was prescribed based solely upon the presence of gross residual tumor. Only one case of G3 toxicity was reported, which was a bilateral pneumonitis that occurred two years after treatment probably due to superinfection. Median Time to Progression reached 18.2 months while one- and three-year Overall Survival rates were 85% (95% CI:60.4-94.9) and 49.5% (95% CI:26.5-68.9), respectively. Treatment of the intact lung with pleural intensity-modulated arc irradiation is a novel treatment strategy that appears to be safe, feasible, and without a high grade of lung toxicity. Survival rates and Time to Progression are encouraging.

Keywords:  OS; hypofractionation; mesothelioma; pulmonary cancer; radiation pneumonitis; radiotherapy; tomotherapy; toxicity

DOI:  https://doi.org/10.3390/cancers15041057
Biosci Biotechnol Biochem. 2023 Feb 21. pii: zbad022. [Epub ahead of print]

Identification of a derivative of the alkaloid emetine as an inhibitor of the YAP-TEAD interaction and its potential as an anticancer agent.

Saaya Sekine, Shohei Takase, Runa Hayase, Kota Noritsugu, Yuki Maemoto, Yasue Ichikawa, Kenji Ogawa, Yasumitsu Kondoh, Hiroyuki Osada, Minoru Yoshida, Akihiro Ito.

  TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction.

Keywords:  Anticancer agent; Emetine; Hippo pathway; TEAD; YAP

DOI:  https://doi.org/10.1093/bbb/zbad022
Proc Natl Acad Sci U S A. 2023 Feb 28. 120(9): e2210836120

Defining and targeting tumor-associated macrophages in malignant mesothelioma.

Licun Wu, Mikihiro Kohno, Junichi Murakami, Amin Zia, Jonathan Allen, Hana Yun, Meilin Chan, Cristina Baciu, Mingyao Liu, Veronique Serre-Beinier, Michele De Palma, Emanuela Felley-Bosco, Jonathan Yeung, Trevor J Pugh, Marc de Perrot.

  Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D-/-) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial-mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, TREM2, STAB1, LAIR1, GPNMB, and MARCO, could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.

Keywords:  cancer; gene signature; mesothelioma; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1073/pnas.2210836120