Role of MIF/CD74 signaling pathway in the development of pleural mesothelioma

Our plain-English summary of Role of MIF/CD74 signaling pathway in the development of pleural mesothelioma, by C. D'Amato-Brito, D. Cipriano, D.J. Colin, et al (Oncotarget, 2016).

The study

• Authors: C. D'Amato-Brito, D. Cipriano, D.J. Colin, S. Germain, Y. Seimbille, J.H. Robert, F. Triponez, V. Serre-Beinier
• Journal: Oncotarget
• Published: 2016;7(10):11512-25
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine implicated in acute and chronic inflammatory diseases. MIF is overexpressed in various tumors. It displays a number of functions that provide a direct link between the process of inflammation and tumor growth. Our group recently identified the MIF-receptor CD74 as an independent prognostic factor for overall survival in patients with malignant pleural mesothelioma.In the present study, we compared the levels of expression of MIF and CD74 in different human mesothelioma cell lines and investigated their physiopathological functions in vitro and in vivo.Human mesothelioma cells expressed more CD74 and secreted less MIF than non tumoral MeT5A cells, suggesting a higher sensitivity to MIF. In mesothelioma cells, high MIF levels were associated with a high multiplication rate of cells. In vitro, reduction of MIF or CD74 levels in both mesothelioma cell lines showed that the MIF/CD74 signaling pathway promoted tumor cell proliferation and protected MPM cells from apoptosis. Finally, mesothelioma cell lines expressing high CD74 levels had a low tumorigenic potential after xenogeneic implantation in athymic nude mice.All these data highlight the complexity of the MIF/CD74 signaling pathway in the development of mesothelioma.

In plain English

This laboratory study of cells and mice did not study asbestos exposure or patients. The authors examined MIF, an inflammation-related protein, and its receptor CD74 in six human malignant pleural mesothelioma cell lines and compared them with a non-tumorigenic mesothelial cell line, MeT5A. CD74 gene expression was significantly higher in all six lines than in MeT5A. All six secreted less MIF, from 2-fold lower (H28) to 14-fold lower (JL-1). Gene silencing of MIF in the H28 and H2052 lines lowered cell multiplication by 39% and 40%. Reducing CD74 lowered multiplication by 29% (H28) and 49% (H2052), and apoptosis (programmed cell death) rose. Four lines were injected into immune-deficient mice. The low-CD74 lines MSTO and JL-1 and high-CD74 line H2052 formed tumours under the skin in 10/10, 7/7 and 5/6 mice. The high-CD74 line H28 formed none within 155 days. The authors concluded that CD74 expression was negatively associated with tumour formation in the mice and that the MIF/CD74 pathway has a complex role. They noted that the under-the-skin site is not representative of the environment where the tumour originated.

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: Laboratory study of human mesothelioma cell lines (in vitro) plus an animal experiment in which the cells were implanted into athymic nude mice
• Who was studied: Six human malignant pleural mesothelioma cell lines (JL-1, DM-3, H28, H2052, H2452, MSTO) and a non-tumorigenic immortalised mesothelial cell line (MeT5A). Four of the mesothelioma lines (MSTO, JL-1, H2052, H28) were injected under the skin and into the pleural cavity of athymic female nude mice.
• Exposure: No asbestos exposure was studied. The experimental factor was the level of MIF and its receptor CD74, which the authors reduced in the H28 and H2052 cell lines using small interfering RNA (siRNA).
• Main results:
  • CD74 mRNA expression was significantly higher in all six mesothelioma cell lines than in the MeT5A mesothelial cell line.
  • All mesothelioma cell lines secreted significantly less MIF than MeT5A. The difference ranged from 2-fold lower (H28) to 14-fold lower (JL-1).
  • Reducing MIF with siRNA reduced the cell multiplication rate by 39% in H28 cells and 40% in H2052 cells, compared with control-treated cells.
  • After MIF reduction, apoptosis was measured at 213% (H28) and 334% (H2052) of the level in control-treated cells.
  • CD74 siRNA reduced CD74 expression by 96% in H28 cells and 98% in H2052 cells.
  • Reducing CD74 with siRNA reduced the cell multiplication rate by 29% in H28 cells and 49% in H2052 cells, compared with control-treated cells, and apoptosis increased.
  • In nude mice, tumours formed under the skin in 10/10 mice injected with MSTO cells, 7/7 with JL-1 cells and 5/6 with H2052 cells. MSTO and JL-1 had been described as low-CD74 lines and H2052 as a high-CD74 line.
  • Pleural tumours were identified by PET/CT in 9/10 mice injected with MSTO cells, 5/10 with JL-1 cells and 5/6 with H2052 cells.
  • Mice injected with the high-CD74 line H28 developed no tumours, under the skin or in the pleura, up to 155 days after injection.
• The authors' conclusion: The authors concluded that the mouse data suggested CD74 expression was negatively associated with tumour formation in pleural mesothelioma, and that the data showed a complex role for the MIF/CD74 pathway in mesothelioma development.
• Limitations the authors state:
  • The authors noted that the under-the-skin graft site is not representative of the environment in which the tumour originated.
  • The authors could not detect CD74 on the surface of the mesothelioma cells using flow cytometry.

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, Macrophage, Cytokine, Inflammation, Overall Survival, Mesothelioma, Apoptosis.

Related studies

• Differential regulation of the sphere formation and maintenance of cancer-initiating cells of malignant mesothelioma via CD44 and ALK4 signaling pathways — Y. Ohno, S. Shingyoku, et al. (2018)
• Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway — T. Chen, H. Nie, et al. (2014)
• CD74: a new prognostic factor for patients with malignant pleural mesothelioma — C. Otterstrom, A. Soltermann, et al. (2014)
• CK2α, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells — S. Zhang, Y.L. Yang, et al. (2014)
• AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy — Z. Lin, T. Liu, et al. (2014)
• S100A11 is involved in the progression of colorectal cancer through the desmosome-catenin-TCF signaling pathway — J. Zhou, H. Murata, et al. (2024)

Browse more research in Oncotarget, or return to medical research.