Use of an antagonist of HMGB1 in mice affected by malignant mesothelioma: a preliminary ultrasound and optical imaging study

Our plain-English summary of Use of an antagonist of HMGB1 in mice affected by malignant mesothelioma: a preliminary ultrasound and optical imaging study, by M. Venturini, R. Mezzapelle, S. La Marca, et al (European Radiology Experimental, 2022).

The study

• Authors: M. Venturini, R. Mezzapelle, S. La Marca, L. Perani, A. Spinelli, L. Crippa, A. Colarieti, A. Palmisano, P. Marra, A. Coppola, F. Fontana, G. Carcano, C. Tacchetti, M. Bianchi, A. Esposito, M.P. Crippa
• Journal: European Radiology Experimental
• Published: 2022;6(1):7
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is an aggressive tumor, with a poor prognosis, usually unresectable due to late diagnosis, mainly treated with chemotherapy. BoxA, a truncated form of "high mobility group box 1" (HMGB1), acting as an HMGB1 antagonist, might exert a defensive action against MM. We investigated the potential of BoxA for MM treatment using experimental 40-MHz ultrasound and optical imaging (OI) in a murine model.

Methods: Murine MM cells infected with a lentiviral vector expressing the luciferase gene were injected into the peritoneum of 14 BALB/c mice (7 × 104 AB1-B/c-LUC cells). These mice were randomized to treatment with BoxA (n = 7) or phosphate-buffered saline (controls, n = 7). The experiment was repeated with 40 mice divided into two groups (n = 20 + 20) and treated as above to confirm the result and achieve greater statistical power. Tumor presence was investigated by experimental ultrasound and OI; suspected peritoneal masses underwent histopathology and immunohistochemistry examination.

Results: In the first experiment, none of the 7 controls survived beyond day 27, whereas 4/7 BoxA-treated mice (57.1%) survived up to day 70. In the second experiment, 6/20 controls (30.0%) and 16/20 BoxA-treated mice (80.0%) were still alive at day 34 (p = 0.004). In both experiments, histology confirmed the malignant nature of masses detected using experimental ultrasound and OI.

Conclusion: In our preclinical experience on a murine model, BoxA seems to exert a protective role toward MM. Both experimental ultrasound and OI proved to be reliable techniques for detecting MM peritoneal masses.

© 2022. The Author(s) under exclusive licence to European Society of Radiology.

In plain English

This was a laboratory experiment in mice. It did not study people or asbestos exposure. The authors injected mouse mesothelioma cells into the abdominal cavity of BALB/c mice. The mice were then treated every other day with either BoxA, a shortened form of the protein HMGB1 that acts against HMGB1, or a salt solution (controls). Tumors were tracked with ultrasound and light-based optical imaging, and suspected masses were examined under the microscope. In a first experiment, none of 7 controls survived beyond day 27, while 4 of 7 BoxA-treated mice (57.1%) survived up to day 70. In a second experiment, 6 of 20 controls (30.0%) and 16 of 20 BoxA-treated mice (80.0%) were alive at day 34 (p = 0.004). In that experiment, ultrasound found masses in 16 of 20 controls and 5 of 20 treated mice. Microscope findings matched the imaging. The authors concluded that BoxA protected against mesothelioma in this mouse model. They said further preclinical studies were needed before moving to people.

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: two randomized treatment-versus-control experiments in a mouse model of peritoneal malignant mesothelioma, with tumors monitored by experimental 40-MHz ultrasound and optical (bioluminescence) imaging and checked by histology
• Who was studied: BALB/c mice: 14 in a first preliminary experiment (7 BoxA-treated, 7 controls) and 40 in a second experiment (20 BoxA-treated, 20 controls), at animal facilities of Ospedale S. Raffaele and Istituto di Ricerche Farmacologiche "Mario Negri" (Milan, Italy). Study dates are not given.
• Exposure: No asbestos was used. Mesothelioma was induced by injecting murine mesothelioma cells engineered to carry the luciferase gene (AB1-B/c-LUC) into the peritoneum. The treatment was BoxA wild type, an HMGB1 antagonist: 400 μL at 2 mg/mL (800 μg, 32 mg/kg), given intraperitoneally every other day for 28 days in the first experiment and 33 days in the second. Controls received 400 μL of phosphate-buffered saline.
• Main results:
  • First experiment: none of the 7 control mice survived beyond day 27, whereas 4 of 7 BoxA-treated mice (57.1%) survived up to day 70. No malignant masses were found at necropsy in these survivors.
  • Second experiment: 6 of 20 control mice (30.0%) and 16 of 20 BoxA-treated mice (80.0%) were alive at day 34, when treatment was stopped (p = 0.004, Fisher exact test).
  • Second experiment: two days after treatment stopped, survival was 20% for control mice and 75% for BoxA-treated mice.
  • Second experiment: 2 control and 6 BoxA-treated surviving mice were injected again with mesothelioma cells at day 61. All surviving mice, rechallenged or not, lived to the end of the experiment, which the authors said suggested tumor rejection.
  • First experiment ultrasound: masses were seen in 4 of 7 BoxA-treated mice and 7 of 7 controls (p = 0.192, not statistically significant).
  • Second experiment ultrasound: abdominal masses were seen in 5 of 20 BoxA-treated mice and 16 of 20 controls (p = 0.001, Fisher exact test).
  • Second experiment optical imaging: 16 of 20 (80%) BoxA-treated mice showed a stable signal reduction of at least one order of magnitude, and all of them survived to the 6th scan. Among controls, 6 of 20 (30%) showed such a reduction, and these were the only controls that survived to the 6th scan.
  • Histology: in both experiments, mice that were negative on both optical imaging and ultrasound were also negative on histology, and mice positive on both were also positive on histology.
• The authors' conclusion: The authors concluded that, in their preclinical experience in a murine model, BoxA exerted a protective role on malignant mesothelioma and may represent an immunotherapeutic strategy. They added that further preclinical studies are needed. They also concluded that combined ultrasound and optical imaging allowed detection of tumor onset and growth in each animal.
• Limitations the authors state:
  • The authors stated that the findings are preliminary and need confirmation in further preclinical studies before BoxA is moved to a clinical setting.
  • The authors stated that optical imaging is not a completely quantitative method, because emitted light is attenuated by overlying tissue.
  • The authors stated that both experimental ultrasound and optical imaging are operator-dependent.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Mesothelioma, Ultrasound, Prognosis, Unresectable, Chemotherapy, Peritoneum, Histopathology.

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• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma — L. Pellegrini, J. Xue, et al. (2017)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)

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