Pre-clinical Models for Malignant Mesothelioma Research: From Chemical-Induced to Patient-Derived Cancer Xenografts

Our plain-English summary of Pre-clinical Models for Malignant Mesothelioma Research: From Chemical-Induced to Patient-Derived Cancer Xenografts, by N. Nabavi, J. Wei, D. Lin, et al (Frontiers in Genetics, 2018).

The study

• Authors: N. Nabavi, J. Wei, D. Lin, C.C. Collins, P.W. Gout, Y. Wang
• Journal: Frontiers in Genetics
• Published: 2018;9:232
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a rare disease often associated with environmental exposure to asbestos and other erionite fibers. MM has a long latency period prior to manifestation and a poor prognosis. The survival post-diagnosis is often less than a year. Although use of asbestos has been banned in the United States and many European countries, asbestos is still being used and extracted in many developing countries. Occupational exposure to asbestos, mining, and migration are reasons that we expect to continue to see growing incidence of mesothelioma in the coming decades. Despite improvements in survival achieved with multimodal therapies and cytoreductive surgeries, less morbid, more effective interventions are needed. Thus, identifying prognostic and predictive biomarkers for MM, and developing novel agents for targeted therapy, are key unmet needs in mesothelioma research and treatment. In this review, we discuss the evolution of pre-clinical model systems developed to study MM and emphasize the remarkable capability of patient-derived xenograft (PDX) MM models in expediting the pre-clinical development of novel therapeutic approaches. PDX disease model systems retain major characteristics of original malignancies with high fidelity, including molecular, histopathological and functional heterogeneities, and as such play major roles in translational research, drug development, and precision medicine.

In plain English

This article is a mini review, not a new study. The authors described laboratory models used to study malignant mesothelioma. They summarized older work in which rats, mice or hamsters were injected with asbestos fibers into the chest or abdominal cavity. A cited 1991 study reported that tumors appeared after about 7 months in mice and 12 months in rats. They covered Simian virus 40 (SV40), whose role as a cause they called controversial but which they described as a cofactor with asbestos in animal models. They also covered genetically modified mice. Mice lacking the Nf2 gene developed mesothelioma faster after asbestos exposure, and developed invasive pleural mesothelioma without asbestos when other genes were also missing. The review also covered cell lines grown from patients' tumors, and patient-derived xenografts, in which patients' tumor tissue is grown in mice with weakened immune systems. In one cited study, xenografts formed from 20 of 50 (40%) tumors, and formation was associated with poor patient survival. The authors concluded that patient-derived xenografts are invaluable research platforms, while noting challenges such as cost and failed grafting.

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: Mini review of pre-clinical (laboratory) models of malignant mesothelioma; no new data were collected
• Who was studied: No human study population. The review covered laboratory models: asbestos-exposed rats, mice and hamsters, genetically modified mice, cell lines from mesothelioma patients, and patient tumors grown in immunodeficient mice
• Exposure: In the models reviewed: asbestos fibers of varying doses and sizes injected into the chest (intrapleural) or abdominal (intraperitoneal) cavity of animals, or added to mesothelial cells. Also SV40 virus, and gene changes (for example loss of Nf2, p53, Ink4a/Arf)
• Main results:
  • Cited study (Suzuki, 1991): asbestos-induced mesothelioma models appeared after long latency periods of about 7 months in mice, 12 months in rats, and years in primates
  • The authors stated that SV40's role as a cause of mesothelioma is controversial, but that its role as a cofactor with asbestos has been established in animal models
  • Cited study (Altomare et al., 2005): Nf2 knockout mice exposed to asbestos showed accelerated mesothelioma tumor formation
  • Cited studies: Nf2-deficient mice crossed with Ink4a/Arf-deficient or p53-deficient mice developed invasive pleural mesothelioma with short median survival, without any asbestos exposure
  • Cited study (Wu et al., 2017): tumors from 50 patients were implanted into immunodeficient mice; xenografts formed in 20 of 50 (40%), and xenograft formation was associated with poor patient survival
  • Cited study (Darai-Ramqvist et al., 2013): in patient-derived xenografts, the sarcomatoid subtype grew faster than the epithelioid subtype
  • Cited study (Kalra et al., 2015): in xenografts made from mesothelioma cells taken from patients' ascites or pleural fluid, BAP1 loss correlated with enhanced tumor growth
• The authors' conclusion: The authors concluded that, despite challenges, patient-derived xenograft models are invaluable for studying how mesothelioma starts, grows and spreads, and for testing treatments. They added that new models that develop mesothelioma spontaneously are still needed
• Limitations the authors state:
  • The authors noted challenges of the patient-derived xenograft models themselves: cost, grafts that fail, and results that may not translate efficiently to clinical protocols
  • The authors noted that cell lines cannot precisely reflect conditions in the body, such as tumor heterogeneity and the tumor microenvironment
  • The authors noted that very few animal studies have taken the genomic background of mesotheliomas into account when exploring targeted therapy

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Environmental Exposure, erionite, Latency, Prognosis, Occupational Exposure, Mesothelioma, Cytoreductive Surgery.

Related studies

• Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model — Y. Wang, J.Y. Perentes, et al. (2012)
• Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients — R. Affatato, P. Mendogni, et al. (2020)
• Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model — J.M. Hillegass, A. Shukla, et al. (2010)
• Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model — S. Abe, M.K. Kaneko, et al. (2016)
• Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models — K. Wickstroem, U.B. Hagemann, et al. (2019)
• Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma — M.J. Lathrop, E.K. Sage, et al. (2015)

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