Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice

Our plain-English summary of Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice, by D.J. Colin, O. Bejuy, S. Germain, et al (Journal of Visualized Experiments, 2019).

The study

• Authors: D.J. Colin, O. Bejuy, S. Germain, F. Triponez, V. Serre-Beinier
• Journal: Journal of Visualized Experiments
• Published: 2019
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor arising in the mesothelium that covers the lungs, the heart, and the thoracic cavity. MPM development is mainly associated with asbestos. Treatments provide only modest survival since the median survival average is 9-18 months from the time of diagnosis. Therefore, more effective treatments must be identified. Most data describing new therapeutic targets were obtained from in vitro experiments and need to be validated in reliable in vivo preclinical models. This article describes one such reliable MPM orthotopic model obtained after injection of a human MPM cell line H2052/484 into the pleural cavity of immunodeficient athymic mice. Transplantation in the orthotopic site allows studying the progression of tumor in the natural in vivo environment. Positron emission tomography/computed tomography (PET/CT) molecular imaging using the clinical [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) radiotracer is the diagnosis method of choice for examining patients with MPM. Accordingly, [18F]FDG-PET/CT was used to longitudinally monitor the disease progression of the H2052/484 orthotopic model. This technique has a high 3R potential (Reduce the number of animals, Refine to lessen pain and discomfort, and Replace animal experimentation with alternatives) since the tumor development can be monitored non-invasively and the number of animals required could be significantly reduced. This model displays a high development rate, a rapid tumor growth, is cost-efficient and allows for rapid clinical translation. By using this orthotopic xenograft MPM model, researchers can assess biological responses of a reliable MPM model following therapeutic interventions.

In plain English

This was a laboratory methods article describing a mouse model of mesothelioma. It did not study people or asbestos exposure. Researchers in Geneva, Switzerland injected one million cells of a human malignant pleural mesothelioma cell line, H2052/484, into the chest (pleural) cavity of female athymic nude mice, which lack mature T cells. They then scanned the mice weekly by [18F]FDG-PET/CT imaging. The authors reported 1 death among 266 mice injected with different mesothelioma cell lines. Of mice injected with H2052/484, 93.8% developed tumors (n = 118). Tumors could be detected from 14 days after injection. Citing another study, the authors added that the tumors were located in the chest cavity and no metastases were found. In a representative time course of 6 mice, lung volume on CT fell over time (R squared 0.8) and tumor tracer uptake rose (R squared 0.7). The authors concluded that the model, with this imaging, is a valuable and reproducible method for studying new diagnostic strategies and treatments. They noted it cannot be used for treatments needing a complete immune response, such as T-cell immunotherapies.

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 presented as a methods (protocol) article: an orthotopic xenograft model, in which human mesothelioma cells were implanted in the mouse pleural cavity, monitored by PET/CT imaging
• Who was studied: Eight to ten-week-old athymic female nude mice (Foxn1nu nu/nu), studied at the University Hospitals and University of Geneva, Switzerland. 266 mice were injected with different mesothelioma cell lines. For the H2052/484 line, n = 118. The imaging time courses used n = 6.
• Exposure: No asbestos or fiber exposure was studied. Each mouse received an injection of 1 x 10 to the 6th (one million) cells of the human malignant pleural mesothelioma cell line H2052/484 in 50 microliters, into the pleural cavity between the 6th and 7th ribs. The mice were then imaged weekly by [18F]FDG-PET/CT starting on day 7.
• Main results:
  • Among 266 mice injected with different mesothelioma cell lines using this protocol, 1 died.
  • No pneumothorax or implantation of tumor cells into the lung was observed among the 266 injected mice.
  • For the H2052/484 cell line, 93.8% of injected mice developed tumors (n = 118).
  • H2052/484 tumors could be detected by PET/CT from 14 days after injection. The authors also gave a median experiment duration of 31 days in a representative experiment, which they cite to another reference (reference 21).
  • Citing 'this other study' (reference 21), the authors reported that the tumors were located in the thoracic cavity and that metastases were not found. This was not presented as an assessment made in this methods article.
  • In a representative time course of 6 mice, lung volume measured by CT was inversely correlated with time after injection (R squared 0.8).
  • Tumor uptake of [18F]FDG (SUVmax) was positively correlated with time after injection (R squared 0.7).
  • Lung volume on CT and [18F]FDG uptake on PET correlated with each other (R squared 0.6).
• The authors' conclusion: The authors concluded that, coupled with [18F]FDG-PET/CT imaging, the model is a valuable and reproducible method for studying new diagnostic strategies and treatments for human malignant pleural mesothelioma.
• Limitations the authors state:
  • Because nude mice are deficient in T cells, studies that require a complete immune response, such as immunotherapies involving a T-cell response, cannot be done in this model.
  • Compared with optical imaging, PET/CT uses radioactive compounds and is harder to set up because of safety, the logistics of radiotracers and cost.
  • Reading [18F]FDG-PET scans may require experience because of high tracer uptake in the nearby heart and brown adipose tissue.

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, Mesothelium, Median Overall Survival, Pleural Cavity, Disease Progression.

Related studies

• Experimental Model of Human Malignant Mesothelioma in Athymic Mice — D.J. Colin, D. Cottet-Dumoulin, et al. (2018)
• Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor — E. Nakataki, S. Yano, et al. (2006)
• 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)
• SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model — T.T. Van, M. Hanibuchi, et al. (2012)
• Progressive growth of a human pleural mesothelioma xenografted to athymic rats and mice — C.J. Lindén, L. Johansson (1988)
• Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model — A.S. Abu Lila, C. Kato, et al. (2016)

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