Use of preclinical models for malignant pleural mesothelioma

Our plain-English summary of Use of preclinical models for malignant pleural mesothelioma, by M. Shamseddin, J. Obacz, M.J. Garnett, et al (Thorax, 2021).

The study

• Authors: M. Shamseddin, J. Obacz, M.J. Garnett, R.C. Rintoul, H.E. Francies, S.J. Marciniak
• Journal: Thorax
• Published: 2021;76(11):1154-1162
• Type of article: Review
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12-18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

In plain English

This was a state-of-the-art review of laboratory models used to study malignant pleural mesothelioma (MPM). The authors described two-dimensional cell lines from primary tumours and pleural effusions, three-dimensional spheroids and microfluidic 'tumour on a chip' systems, genetically engineered mice, asbestos- and carbon-nanotube-induced rodent models, patient-derived xenografts and syngeneic murine models, and set out reported strengths and weaknesses of each. Among the figures reviewed were cell line establishment success rates of 20% to 84%; mesothelioma in 17%, 22% and 63% of mice after homozygous co-deletion of Bap1;Nf2, Bap1;Ink4a/Arf and Nf2;Ink4a/Arf respectively, rising to 85% when all three genes were targeted; pleural mesothelioma in 10%-25% of mice given long-fibre carbon nanotubes into the pleural cavity compared with 9% of mice injected with asbestos; and a 40% engraftment rate for xenografts from 50 MPM patients. The authors concluded that current preclinical models may not sufficiently recapitulate human physiology, that no single model has every ideal feature, and that organoid technology has not yet been applied to MPM.

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 state-of-the-art review of preclinical in vitro and in vivo models of malignant pleural mesothelioma
• Who was studied: Published preclinical models of MPM: human cell lines from tumour tissue and pleural effusions, spheroids and microfluidic chips, genetically modified and asbestos-exposed mice and rats, patient-derived xenografts and syngeneic murine models
• Exposure: Asbestos fibres (the stated main cause of MPM in patients, and used experimentally by intraperitoneal, intrapleural or inhalation routes in rodents) and carbon nanotubes; also genetic alterations introduced into mice
• Main results:
  • Reported success rates for establishing human MPM cell lines from tumour tissue and pleural effusions ranged from 20% to 84%
  • In conditional knockout mice, mesotheliomas followed homozygous co-deletion of Bap1;Nf2 in 17%, Bap1;Ink4a/Arf in 22% and Nf2;Ink4a/Arf in 63% of mice, and 85% when all three genes were targeted
  • In wild-type mice, long-fibre carbon nanotubes injected into the pleural cavity caused pleural mesothelioma in 10%-25% of animals, compared with 9% of mice injected with asbestos; in rats, multiwalled carbon nanotubes gave pleural and pericardial mesothelioma in 16% between 24 and 27 months
  • A patient-derived xenograft bank from fresh tumour material of 50 MPM patients had an engraftment rate of 40%
  • In those xenografts, most sarcomatoid and biphasic samples engrafted but only one-third of epithelioid samples did, and those came from patients with a poorer outcome
  • Cisplatin inhibited growth of 7 of 10 tested PDXs, while pemetrexed alone or combined with cisplatin did not affect growth, attributed to folate metabolism in the mouse strain
• The authors' conclusion: The authors concluded that existing preclinical MPM models do not recapitulate human physiology well enough and/or are too few to capture disease diversity, that model choice should be driven by the aim of the study, and that organoids, not yet applied to MPM, offer hope for the future
• Limitations the authors state:
  • The authors state that cell lines adapt to 2D culture, fail to reproduce tumour heterogeneity and lack immune and stromal interactions
  • The authors state that most cell line studies did not compare the lines with the tumours they came from
  • The authors state that no long-term spheroid models allowing cell expansion currently exist and that spheroid genomic stability has not been compared with the original tumour
  • The authors state that patient-derived xenografts lack an immune system, limiting their use for testing immunotherapies, and that subcutaneous grafting changes the tumour microenvironment
  • The authors state that the long latency of the carbon nanotube/asbestos model makes it unsuitable for drug testing and that the rat model is not yet extensively characterised molecularly
  • The authors state that differing tumour subtypes reported from the same double and triple knockout mice in different studies may complicate interpretation
  • The authors state that animal models are time-consuming and costly and unsuitable for large-scale phenotypic screens

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, Median Survival, Chemotherapy.

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