Macrophage Migration Inhibitory Factor Promotes the Interaction between the Tumor, Macrophages, and T Cells to Regulate the Progression of Chemically Induced Colitis-Associated Colorectal Cancer

Abstract

Colitis-associated colorectal cancer (CRC) development has been shown to be related to chronically enhanced inflammation. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that favors inflammatory cytokine production and has chemotactic properties for the recruitment of macrophages (Møs) and T cells. Here, we investigated the role of MIF in the inflammatory response and recruitment of immune cells in a murine model of chemical carcinogenesis to establish the impact of MIF on CRC genesis and malignancy. We used BALB/c MIF-knockout (MIF-/-) and wild-type (WT) mice to develop CRC by administering intraperitoneal (i.p.) azoxymethane and dextran sodium sulfate in drinking water. Greater tumor burdens were observed in MIF-/- mice than in WT mice. Tumors from MIF-/- mice were histologically identified to be more aggressive than tumors from WT mice. The localization of MIF suggests that it is also involved in cell differentiation. The relative gene expression of il-17, measured by real-time PCR, was higher in MIF-/- CRC mice, compared to the WT CRC and healthy MIF-/- mice. Importantly, compared to the WT intestinal epithelium, lower percentages of tumor-associated Møs were found in the MIF-/- intestinal epithelium. These results suggest that MIF plays a role in controlling the initial development of CRC by attracting Møs to the tumor, which is a condition that favors the initial antitumor responses.

A high monocyte-to-lymphocyte ratio predicts poor prognosis in patients with radical cystectomy for bladder cancer

“…It was reported that hemogram parameters can be used to predict the prognosis of cancer and provide a basis for judging the prognosis of cancer ( 15 , 16 ), and inflammation is related to the occurrence and development of cancer ( 17 , 18 ). A series of inflammatory indexes have been reported to participate in tumor progress, such as MLR, NLR and PLR.…”

Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention

“…The pathophysiological role of MIF in a wide range of inflammatory diseases, among which IBD, was already demonstrated (Nishihira and Mitsuyama, 2009). Increased MIF in macrophages in a CRC mouse model was demonstrated, and loss of MIF expression protects mice during tumor initiation (Pacheco-Fernández et al, 2019;Klemke et al, 2021). In cancer cells from CRC patients and in an acute colitis-CRC mouse model, a tumor-specific elevation of MIF expression was demonstrated (Klemke et al, 2021).…”

Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational Risks from Mechanisms to Medicines

“… 60 Macrophage migration inhibitory factor [MIF] mediates macrophage and T-cell recruitment and MIF −/− mice treated with AOM/DSS have an increased tumour burden, associated with lower levels of macrophages. 61 Fibrinogen-like protein 2 [Fgl2] may be important for macrophage recruitment with/without polarization as Fgl2 loss induces M1-polarized and suppresses M2-polarized macrophages; Fgl2 may therefore reduce inflammation and IBD-CRC. 62 In contrast, TGFβ promotes macrophage recruitment through expression of CCR2 in the tumour microenvironment, and myeloid-cell TGFβ2 expression worsens AOM/DSS-induced tumorigenesis.…”