Myeloid Cell Mobilization and Recruitment by Human Mesothelioma in NSG-SGM3 Mice

Our plain-English summary of Myeloid Cell Mobilization and Recruitment by Human Mesothelioma in NSG-SGM3 Mice, by V.V. Shindyapin, E.O. Gubernatorova, E.A. Gorshkova, et al (Cells, 2024).

The study

• Authors: V.V. Shindyapin, E.O. Gubernatorova, E.A. Gorshkova, N.R. Chicherina, F.A. Sysonov, A.S. Yakovleva, D.A. Bogdanova, O.N. Demidov, M.V. Samsonova, V.P. Baklaushev, G.M. Yusubalieva, M.S. Drutskaya
• Journal: Cells
• Published: 2024;13(24)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is a neoplasm that is often detected late due to nonspecific symptoms. This study utilized NSG-SGM3 mice to examine interactions between a human-derived mesothelioma reporter cell line (MZT-Luc2-mCherry) and the host's myeloid compartment. Tumor growth was assessed using optical tomography, while cytokine/chemokine production was analyzed via multiplex assay. Histological and immunohistochemical analyses validated the epithelioid mesothelioma phenotype. In vitro mesothelioma cells secreted factors associated with myeloid cell chemoattraction and functions supporting the previously reported myeloid-biased secretory phenotype. In line with this, post-engraftment analysis revealed increased neutrophil-like Ly6G+ populations and decreased Ly6C+ inflammatory monocytes in the blood of tumor-bearing mice. Significant Ly6G+ cell infiltration was observed in the tumor, while CD11b+ myeloid cells were localized primarily in the tumor periphery. Tumor lysates showed increased levels of neutrophil chemoattractants and G-CSF, suggesting a previously not reported role of neutrophils in mesothelioma progression. This novel model provides a platform for studying mesothelioma-host interactions, focusing on the myeloid compartment. It may also serve as a tool to facilitate the development of new therapeutic strategies targeting myeloid cell-mediated mechanisms in mesothelioma.

In plain English

This was a laboratory study in mice. The authors established a primary cell line (MZT-Luc2-mCherry) from the pleural biopsy of a patient with epithelioid malignant pleural mesothelioma, labelled it with mCherry and Luc2 luciferase, and injected 2.5 x 10^5 cells subcutaneously into immunodeficient NSG-SGM3 mice. In culture, the mesothelioma cells produced significantly more G-CSF, GM-CSF, IL-8, CXCL1 and IL-1alpha than glioblastoma and acute myeloid leukemia cell lines, while CCL2, CCL3, CCL4 and CCL7 were lower. Naive NSG-SGM3 mice had lower blood CD45+ counts than C57BL/6 mice (p < 0.0001) but a higher percentage of CD11b+ cells within CD45+ cells (p < 0.0001). All injected mice developed tumours; histology and immunohistochemistry were consistent with epithelioid mesothelioma, and no metastatic lesions were detected over 30 days. After engraftment, the proportion of Ly6G+ neutrophil-like cells among blood CD11b+ cells increased and the proportion of Ly6C+ monocyte-like cells decreased (paired t-test, p < 0.0001); Ly6G+ cells infiltrated the tumour core while CD11b+ cells lay mainly at the periphery. Human IL-8 and murine G-CSF and GM-CSF were raised in tumour-bearing mice.

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: human mesothelioma cell line xenografted subcutaneously into immunodeficient mice, with in vitro cytokine profiling
• Who was studied: NSG-SGM3 mice (naive and tumour-bearing; n = 17 imaged, n = 5 caliper-measured, n = 6 naive serum, n = 10 tumour-bearing serum), compared with C57BL/6 mice; the tumour cells came from one patient's pleural biopsy; work done in Russia, ethics approvals 2017 and 2024
• Exposure: subcutaneous engraftment of 2.5 x 10^5 human mesothelioma MZT-Luc2-mCherry cells in 6-8-week-old NSG-SGM3 mice (no asbestos exposure was studied; asbestos is mentioned only as background in the introduction)
• Main results:
  • In vitro, the mesothelioma cell line secreted significantly more G-CSF, GM-CSF, IL-8, CXCL1 and IL-1alpha than the glioblastoma and acute myeloid leukemia lines
  • Chemokines for monocytes/macrophages were lower in the mesothelioma line than in the two comparison lines
  • The engrafted tumours showed features of epithelioid mesothelioma, with Ki-67 nuclear staining in over 60% of tumour cells (n = 4)
  • Naive NSG-SGM3 mice had significantly lower blood CD45+ cell counts than C57BL/6 mice (p < 0.0001), no significant difference in absolute CD11b+ counts, and a higher percentage of CD11b+ within CD45+ cells (p < 0.0001)
  • All injected mice developed tumours (100% engraftment of the MZT-Luc2-mCherry cells)
  • No metastatic lesions were detected by bioluminescent imaging during the 30-day observation period
  • In tumour-bearing mice, Ly6G+ neutrophil-like cells rose and Ly6C+ monocyte-like cells fell as a percentage of blood CD11b+ cells, compared with naive mice (paired t-test, p < 0.0001)
  • Imaging of tumour sections showed Ly6G+ cells mainly inside the tumour and CD11b+ cells forming a dense layer at the tumour periphery (n = 6 samples)
  • Serum of tumour-bearing mice contained human IL-8, and murine G-CSF, GM-CSF, CCL2, CCL5, TNF, IL-1beta, IL-10 and IL-15 were upregulated; tumour lysates showed raised IL8, Cxcl10, Il1b and Ccl2 expression by real-time PCR
• The authors' conclusion: The authors concluded that their xenograft model reproduced key aspects of human mesothelioma progression, including cytokine production and myeloid cell recruitment, without adaptive immunity, and offers a platform for studying myeloid populations and testing myeloid-targeted therapies
• Limitations the authors state:
  • The mice lack a complete immune system, which the authors say must be considered when translating findings to human disease
  • Species differences in cytokine signalling may affect results; human and mouse G-CSF cross-react while GM-CSF does not
  • Subcutaneous implantation itself can recruit neutrophils, so cells at the implantation site may contribute to the observed infiltration
  • The authors state the findings need validation in other preclinical models

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Neoplasm, Cytokine, Epithelioid.

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