Experimental Model of Human Malignant Mesothelioma in Athymic Mice

Our plain-English summary of Experimental Model of Human Malignant Mesothelioma in Athymic Mice, by D.J. Colin, D. Cottet-Dumoulin, A. Faivre, et al (International Journal of Molecular Sciences, 2018).

The study

• Authors: D.J. Colin, D. Cottet-Dumoulin, A. Faivre, S. Germain, F. Triponez, V. Serre-Beinier
• Journal: International Journal of Molecular Sciences
• Published: 2018;19(7)
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a thoracic aggressive cancer caused by asbestos exposure, which is difficult to diagnose and treat. Here, we characterized an in vivo orthotopic xenograft model consisting of human mesothelioma cells (designed as H2052/484) derived from a pleural NCI-H2052 tumor injected in partially immunodeficient athymic mice. We assessed tumor formation and tumor-dependent patterns of inflammation. H2052/484 cells conserved their mesothelioma phenotype and most characteristics from the parental NCI-H2052 cells. After intra-thoracic injection of H2052/484 cells, thoracic tumors developed in nearly all mice (86%) within 14 days, faster than from parental NCI-H2052 cells. When the mice were euthanized, the pleural lavage fluid was examined for immune cell profiles. The pleural immune cell population increased with tumor development. Interestingly, the proportion of myeloid-derived suppressor cell and macrophage (especially CD206⁺ M2 macrophages) populations increased in the pleural fluid of mice with large mesothelioma development, as previously observed in immunocompetent mice. This reliable orthotopic model recapitulates human mesothelioma and may be used for the study of new treatment strategies.

In plain English

This was a laboratory study in mice and cultured cells, not a study of people; asbestos appears only as background, as the cause of malignant pleural mesothelioma (MPM) and in the mention of asbestos-induced mouse models. The authors derived a human mesothelioma cell line, H2052/484, from a pleural tumour grown in a mouse after injection of parental NCI-H2052 cells, and compared it with the parental line and three other MPM lines. In culture, H2052/484 resembled parental H2052 in vitality and multiplication but showed higher mRNA of SNAIL2, ZEB1 and ZEB2; the differences from the three other lines were not statistically significant. After intrapleural injection of 1 x 10(6) cells into 28 female athymic nude mice, thoracic tumours developed in 24/28 within two weeks on [18F]FDG-PET/CT; median survival was 31 days and no metastases were found. Total pleural cell counts were higher at tumour score 4-6 than at score 1-3 (p = 0.0021), and higher but not significantly so than in mice without tumour (p = 0.1472). Macrophages made up 22.9 ± 8.0% of pleural cells in tumour-free mice and 45.3 ± 7.0% in mice with score 4-6 tumours, a difference the table reports as p = 0.2956. The authors concluded the model is reproducible for testing new MPM treatments.

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: animal experiment (orthotopic xenograft of a human mesothelioma cell line in athymic mice) with accompanying in vitro cell-line characterisation
• Who was studied: 28 19-week-old female athymic nude mice (nu/nu) injected intrapleurally, Geneva, Switzerland; plus cultured human MPM cell lines H2052/484, parental NCI-H2052, H28, JL-1 and MSTO-211H
• Exposure: Not an asbestos exposure study: mice received an intrapleural injection of 1 x 10(6) human H2052/484 mesothelioma cells; asbestos is named in the introduction as the cause of MPM and in reference to asbestos-induced mouse models
• Main results:
  • Thoracic tumours developed in 24 of 28 injected mice and were detectable by PET/CT within 2 weeks
  • Half the mice were killed during the active growth phase; median survival was 31 days
  • Tumours were poorly invasive and no metastases were found in distant organs
  • Parental H2052 cells had given pleural tumours only from day 69 after injection, whereas H2052/484 tumours appeared within 2 weeks
  • The number of pleural cells was higher in mice with tumour score 4-6 than in mice with score 1-3 or without tumour (Table 2 gives 425,358 ± 63,830 at score 4-6, n = 14; 111,068 ± 35,687 at score 1-3, n = 10; 185,942 ± 118,481 without tumour, n = 4; p versus score 1-3 = 0.0021, p versus no tumour = 0.1472)
  • CD11b+F4/80+ macrophages were 22.9 ± 8.0% of total pleural cells in mice without tumour and 45.3 ± 7.0% in mice with tumour development score 4-6
  • In Table 3 the macrophage comparison of score 4-6 with tumour-free mice gave p = 0.2956 and with score 1-3 gave p = 0.3193
  • CD11b+F4/80+CD206+ M2 macrophages rose from 1.6% in mice without tumour to 5.6% in mice with tumour development score 4-6
  • The percentage of CD11b+Gr1+ MDSC was reported as two-fold higher in mice with tumours than in mice without tumours (Table 3 gives 27.7 ± 6.7%, n = 4, versus 51.1 ± 8.1%, n = 9; p = 0.1063)
  • Neutrophils were about fourfold higher as a proportion of pleural cells in tumour-bearing mice than in mice without tumours, independently of tumour score, and the neutrophil-to-lymphocyte ratio was sixfold higher
  • Explanted H2052/484 tumours expressed the mesothelioma markers calretinin and mesothelin, and MIF, CD74 and CD44 were detected
  • Compared with parental H2052 cells, H2052/484 cells had higher mRNA of SNAIL2 (3.3-fold change), ZEB1 (1.9-fold change) and ZEB2 (1.4-fold change); levels were also higher than in the three other MPM lines, and those differences were not statistically significant
• The authors' conclusion: The authors concluded that the orthotopic xenotransplantation model of H2052/484 cells in nude mice is reproducible and can be used to study new MPM treatments, including MIF inhibition
• Limitations the authors state:
  • The authors note the mice are partially immunodeficient, lacking T lymphocytes because they have no thymus
  • The authors state that agents tested in this model should then be validated in other mouse models, such as humanized mice
  • The authors describe the tumour cells as only modestly virulent in vivo
  • The in vivo work came from a single experiment in 28 mice

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: Malignant Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Mesothelioma, Inflammation, Macrophage.

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• Progressive growth of a human pleural mesothelioma xenografted to athymic rats and mice — C.J. Lindén, L. Johansson (1988)
• Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model — J.M. Hillegass, A. Shukla, et al. (2010)
• Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin — J. Wörthmüller, V. Salicio, et al. (2019)
• Restored expression of the MYO18B gene suppresses orthotopic growth and the production of bloody pleural effusion by human malignant pleural mesothelioma cells in SCID mice — N. Edakuni, K. Ikuta, et al. (2006)
• Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts — P.M. Tedeschi, Y.K. Kathari, et al. (2014)

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