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.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive cancer of the inner lining of the chest cavity which develops mainly after inhaling asbestos fibers
In order to identify the role of migration inhibitory factor (MIF) in MPM, mRNA and protein levels of MIF-receptors CD74 (Figure 1), CXCR2 and CXCR4 (Figure 2) and MIF (Figure 3), were assessed in six different human MPM cell lines of different histological types (JL-1, DM-3, H28, H2052, H2452 and MSTO) and in an non tumorigenic immortalised mesothelial cell line MeT5A (Table 1)
We have shown that the majority of the malignant mesothelial tumor cells expressed MIF and its receptor CD74, with a homogenous distribution between the different histotypes
Summary
Malignant pleural mesothelioma (MPM) is an aggressive cancer of the inner lining of the chest cavity which develops mainly after inhaling asbestos fibers. While surgery is a valid option for patients with early stage MPM, most patients with locally advanced invasive disease are not amenable to surgical resection [2] and treatment is palliative chemotherapy combining cisplatin and pemetrexed. While this treatment may relieved symptoms, it provides only modest survivals, since median survival averages only 9–18 months from the time of diagnosis
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