Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer

Abstract

Macrophage migration inhibitory factor (MIF) and its receptor CD74 appear to be involved in tumorigenesis. We evaluated, by immunohistochemical staining, the tissue expression and distribution of MIF and CD74 in serial sections of human invasive breast cancer tumor specimens. The serum MIF level was also determined in breast cancer patients. We showed a significant increase in serum MIF average levels in breast cancer patients compared to healthy individuals. MIF tissue expression, quantified by a modified Allred score, was strongly increased in carcinoma compared to tumor-free specimens, in the cancer cells and in the peritumoral stroma, with fibroblasts the most intensely stained. We did not find any significant correlation with histoprognostic factors, except for a significant inverse correlation between tumor size and MIF stromal positivity. CD74 staining was heterogeneous and significantly decreased in cancer cells but increased in the surrounding stroma, namely in lymphocytes, macrophages and vessel endothelium. There was no significant variation according to classical histoprognostic factors, except that CD74 stromal expression was significantly correlated with triple-negative receptor (TRN) status and the absence of estrogen receptors. In conclusion, our data support the concept of a functional role of MIF in human breast cancer. In addition to auto- and paracrine effects on cancer cells, MIF could contribute to shape the tumor microenvironment leading to immunomodulation and angiogenesis. Interfering with MIF effects in breast tumors in a therapeutic perspective remains an attractive but complex challenge. Level of co-expression of MIF and CD74 could be a surrogate marker for efficacy of anti-angiogenic drugs, particularly in TRN breast cancer tumor.

Involvement of macrophage migration inhibitory factor in cancer and novel therapeutic targets

“…In addition, our previous study also revealed that in breast cancer patients, MIF expression was increased in cancer tissues when compared with tumor-free breast tissues in glandular and stromal compartments (12). Therefore, these results provide compelling evidence that MIF is involved in tumor biology.…”

“…In addition to inflammatory diseases, MIF has also been demonstrated to be overexpressed in solid tumors, such as lung, colorectal, breast, cervical, prostate, and head and neck cancer, where it may exhibit a crucial function in tumor progression (cell proliferation and invasiveness) and tumor-induced angiogenesis (10)(11)(12)(13)(14)(15) Globally, the MIF effects in cancer may be mainly explained by signaling through the CD74 receptor, since we recently showed that i) CD74 is upregulated in oral cavity carcinomas compared with benign lesions, ii) knockdown of CD74 in the murine squamous cell carcinoma SCCVII cell line decreases in vitro proliferation, migration, MMP9 secretion and VEGF production, and iii) SCCVII CD74-knockdown cells orthotopically inoculated in mice have a weaker growth capacity than scramble cells (16).…”

Up-Regulation of CD74 Expression in Parietal Epithelial Cells in a Mouse Model of Focal Segmental Glomerulosclerosis

“…By immunohistochemistry, CD74 staining was observed to be co-localized with CD44 in some epithelial cells lining the BC in ADR-injured glomeruli, suggesting a role for CD74 expression in PEC activation. Although recent studies have suggested possible roles for the CD74-CD44 receptor complex and its ligand MIF in tumor cell proliferation [13,14,15,16], their roles in kidney diseases have not been elucidated; therefore, we attempted to evaluate CD74 expression in PEC activation and performed comparative analysis of CD74 and other PEC markers.…”

“…CD74 acts as a cell membrane receptor for the macrophage migration inhibitory factor (MIF), and the formation of the CD44-CD74 complex initiates the signaling pathway triggered by MIF in macrophages [9] and B cells [10,11,12], inducing cell proliferation and survival. Moreover, several studies suggested a role for CD74 expression in the progression of thyroid, breast, pancreatic, skin and gastrointestinal tract cancers [13,14,15,16]; however, only a few studies were conducted to evaluate the role of CD74 expression and that of CD74-CD44 complex in kidney diseases [17,18]. …”

Prognostic value of several biomarkers for the patients with malignant pleural mesothelioma

“…CD74, first identified as a chaperone of major histocompatibility complex (MHC) class II proteins in antigen presentation for the immune response, was subsequently found to be a receptor of macrophage migration inhibitory factor (MIF) that was actively involved in various autoimmune and inflammatory disorders as well as tumorigenesis [62,63]. Recent data have shown that CD74 protein is upregulated in cancer cells, indicating its role in carcinogenesis and angiogenesis [63][64][65][66].…”