The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment

Our plain-English summary of The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment, by V. Galani, A. Varouktsi, S.S. Papadatos, et al (Cancer Chemotherapy and Pharmacology, 2019).

The study

• Authors: V. Galani, A. Varouktsi, S.S. Papadatos, A. Mitselou, I. Sainis, S. Constantopoulos, Y. Dalavanga
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2019;84(2):241-253
• Type of article: Review
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a highly aggressive tumor that is strongly related to asbestos fiber exposure. The tumorigenesis procedure in MM is complex, and many pathogenetic mechanisms including chronic inflammation, deregulation of cell death, and the genomic copy-number losses and gains may contribute to carcinogenesis. MM cells are resistant to TRAIL-mediated apoptosis due to defects in extrinsic apoptotic pathway. CAPS, a regulator of cell cycle and death, may contribute to the MM development as well. BAP1 is the most frequently inactivated gene in MPM; BAP1 deficiency triggers malignant transformation via disruption of DNA repair, transcription regulation, cell metabolism, apoptosis, and ferroptosis. In addition, bcl-2 family proteins as well as abnormal activation of PI3 K/Akt/mTOR pathway and deregulation of the Wnt signaling pathway may result in MM tumorigenesis. Finally, the Hippo pathway plays a critical role in MPM development. Mutations of NF2 and LATS lead to YAP activation in MPM. Thus, inhibition of YAP activity by YAP inhibitors could be a potentially promising treatment option for MM. In conclusion, extensive genetic alterations exist in mesotheliomas associated with the signaling of apoptotic HM cells death. The comprehension of these pathways may contribute to enhancing survival via developing new effective therapeutic strategies.

In plain English

This article was a review, not a new study. The authors gave an overview of published laboratory, animal and patient research on how defects in apoptosis (programmed cell death) may contribute to malignant mesothelioma, and what this might mean for prognosis and treatment. Summarizing earlier work, the review stated that most malignant pleural mesothelioma cells resist apoptosis triggered by a molecule called TRAIL. It also stated that pleural mesothelioma cell lines and tumors rarely express the Bcl-2 protein but normally express Bcl-xl, Bax and Bak. It reported that somatic BAP1 point mutations were found in up to 60% of sporadic mesotheliomas and that loss of BAP1 may confer a better prognosis. It described a mouse study whose authors concluded that minimal exposure to carcinogenic fibers may increase mesothelioma risk in carriers of germline BAP1 mutations. It also cited another study suggesting that mesothelioma develops without asbestos in BAP1 knockout mice. The authors concluded that mesothelioma development is complex and mainly results from deregulated apoptosis, and they called for further studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of published research on apoptosis (cell death) pathways in malignant mesothelioma
• Who was studied: No new population was studied. The review drew on earlier studies of mesothelioma cell lines, tumor tissue samples, mouse models and some patient series.
• Exposure: Asbestos is discussed as background, as a trigger of mesothelial cell death and inflammation. No exposure was measured in this review. One cited mouse study used crocidolite asbestos injected into the abdomen.
• Main results:
  • Summarizing earlier studies, the review stated that although malignant pleural mesothelioma cells express TRAIL receptors, most resist TRAIL-mediated apoptosis because of defects in the extrinsic apoptotic pathway.
  • Cited studies found that pleural mesothelioma cell lines and tumors rarely expressed the antiapoptotic protein Bcl-2, but normally expressed the antiapoptotic protein Bcl-xl and the proapoptotic proteins Bax and Bak.
  • The review reported, from earlier studies, that BAP1 mutations are associated with better prognosis in mesothelioma patients and that somatic BAP1 point mutations were found in up to 60% of sporadic mesotheliomas.
  • Based on cited studies, the review stated that loss of BAP1 may confer a better prognosis.
  • In a cited mouse study (Napolitano et al.), the study's authors concluded that minimal exposure to carcinogenic fibers may increase mesothelioma risk in individuals carrying germline BAP1 mutations.
  • The review also cited a study suggesting that mesothelioma develops without asbestos exposure in BAP1 knockout mice.
  • A cited patient study (Ohar et al.) reported germline BAP1 mutations in 9 of 150 patients with mesothelioma and a family history of cancer.
  • The review authors said the Ohar et al. findings are unclear, because that study did not give details of asbestos exposure, such as dose and latency, or of tumor site.
  • The review stated that mutations of NF2 and LATS lead to YAP activation in pleural mesothelioma, and that YAP inhibitors could be a potentially promising treatment option.
• The authors' conclusion: The authors concluded that tumor development in malignant mesothelioma is complex and mainly results from deregulation of apoptosis. They called for further studies toward new therapeutic approaches.
• Limitations the authors state:
  • The authors noted that live-animal (in vivo) data on how well Map kinase inhibitors work, in patients or even in animal models, are still relatively few.
  • The authors stated that further studies are needed to identify which apoptotic signals go with particular combinations of mutations or deletions.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Malignant Mesothelioma, Prognosis, Tumorigenesis, Chronic Inflammation, Carcinogenesis, BAP1, Malignant Transformation.

Related studies

• Molecular changes in mesothelioma with an impact on prognosis and treatment — D. Jean, J. Daubriac, et al. (2012)
• Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma — A. Baldi, M.T. Piccolo, et al. (2011)
• Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma — L. Arzt, I. Halbwedl, et al. (2017)
• Environmental toxicity, oxidative stress and apoptosis: ménage à trois — R. Franco, R. Sánchez-Olea, et al. (2009)
• Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia — Z. Li, L. Jiang, et al. (2019)
• SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis — R.P. Jablonski, S.J. Kim, et al. (2017)

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