Heterogeneous Contributing Factors in MPM Disease Development and Progression: Biological Advances and Clinical Implications

Our plain-English summary of Heterogeneous Contributing Factors in MPM Disease Development and Progression: Biological Advances and Clinical Implications, by B. Tolani, L.A. Acevedo, N.T. Hoang, et al (International Journal of Molecular Sciences, 2018).

The study

• Authors: B. Tolani, L.A. Acevedo, N.T. Hoang, B. He
• Journal: International Journal of Molecular Sciences
• Published: 2018;19(1)
• Type of article: Review
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) tumors are remarkably aggressive and most patients only survive for 5-12 months; irrespective of stage; after primary symptoms appear. Compounding matters is that MPM remains unresponsive to conventional standards of care; including radiation and chemotherapy. Currently; instead of relying on molecular signatures and histological typing; MPM treatment options are guided by clinical stage and patient characteristics because the mechanism of carcinogenesis has not been fully elucidated; although about 80% of cases can be linked to asbestos exposure. Several molecular pathways have been implicated in the MPM tumor microenvironment; such as angiogenesis; apoptosis; cell-cycle regulation and several growth factor-related pathways predicted to be amenable to therapeutic intervention. Furthermore, the availability of genomic data has improved our understanding of the pathobiology of MPM. The MPM genomic landscape is dominated by inactivating mutations in several tumor suppressor genes; such as CDKN2A; BAP1 and NF2. Given the complex heterogeneity of the tumor microenvironment in MPM; a better understanding of the interplay between stromal; endothelial and immune cells at the molecular level is required; to chaperone the development of improved personalized therapeutics. Many recent advances at the molecular level have been reported and several exciting new treatment options are under investigation. Here; we review the challenges and the most up-to-date biological advances in MPM pertaining to the molecular pathways implicated; progress at the genomic level; immunological progression of this fatal disease; and its link with developmental cell pathways; with an emphasis on prognostic and therapeutic treatment strategies.

In plain English

This article is a review, not an original study. The authors summarized published research on the biology of malignant pleural mesothelioma (MPM). It covered molecular pathways, genetic changes, tumor immunity and stem cell pathways, focusing on possible treatments. The review described direct workplace exposure to asbestos as the established cause, with about 80% of MPM cases linked to it. It did not discuss specific asbestos fiber types. Drawing on other studies, it reported that the genes CDKN2A, BAP1 and NF2 are often inactivated in MPM. It also reported that one study linked a gene methylation pattern to higher asbestos body counts, and that rare inherited BAP1 mutations contribute to a predisposition to mesothelioma. The review cited earlier work from the authors' own laboratory that found GLI1 and GLI2 activation in about 90% of 46 MPM tissue samples. It named cisplatin and pemetrexed as the only FDA-approved chemotherapy drugs specifically for MPM; the other candidate treatments it listed were not yet approved for MPM. The authors concluded that tumors differ from one patient to another, so a one-size-fits-all approach will not work.

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 the biology and treatment of malignant pleural mesothelioma
• Who was studied: No study population of the authors' own. The review covered published laboratory, animal and clinical research on malignant pleural mesothelioma. The authors state only that a literature search was performed, without describing its methods.
• Exposure: Not a study of a specific exposure. The review described direct workplace exposure to asbestos as the established cause of MPM; no fiber types were named. It said other suggested causes (simian virus 40 infection, erionite, radiation) remain controversial.
• Main results:
  • The review stated that approximately 80% of MPM cases can be linked to asbestos, and that males have a four times higher incidence rate than females.
  • Citing other studies, the review reported that the most common gene loss in MPM is homozygous deletion or inactivation of CDKN2A, occurring at a frequency of over 70%. BAP1 is inactivated in over 60% of mesothelioma cases and NF2 is deleted in around 35 to 40% of MPM cases.
  • Citing Christensen et al., the review reported that methylation of the RASSF1 gene in mesothelioma patients was significantly associated with elevated asbestos body counts, which the review interpreted as longer asbestos exposure.
  • Citing other work, the review stated that rare inherited (germline) BAP1 mutations contribute to a predisposition to malignant mesothelioma and other cancers, even without exposure to high levels of asbestos or other carcinogens.
  • Citing an animal study (Altomare et al.), the review reported that asbestos-exposed mice with deletions of one copy of the P16INK4a or P19ARF genes developed mesothelioma earlier and more often than normal littermates.
  • The review cited earlier work by the authors' own group that found abnormal GLI1 and GLI2 activation in about 90% of MPM tissue samples (n = 46).
  • The review stated that cisplatin and pemetrexed are the only two FDA-approved chemotherapy drugs specifically for treating MPM. Citing other studies, it reported a response rate of 41.3% for their combination, the standard treatment.
  • Apart from cisplatin and pemetrexed, which appear in one listed combination with bevacizumab, the candidate therapies in the review's main table had not been approved for MPM.
• The authors' conclusion: The authors concluded that a one-size-fits-all approach will not suffice, because the tumor environment differs from one cancer to another and from one patient to another, and changes in response to treatment.

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: Pleural Mesothelioma, Chemotherapy, Mechanism of Carcinogenesis, Asbestos Exposure, Tumor Microenvironment, Angiogenesis, Apoptosis, Tumor Suppressor Gene.

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• Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma — N. Peshes-Yeloz, L. Ungar, et al. (2019)
• Factor analysis of clinical data from asbestos workers: implications for diagnosis and screening — P. Harber, M. Lew, et al. (1987)
• SV40-induced expression of calretinin protects mesothelial cells from asbestos cytotoxicity and may be a key factor contributing to mesothelioma pathogenesis — T. Henzi, W.V. Blum, et al. (2009)

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