Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer

Abstract

Macrophage migration inhibitory factor (MIF) emerged in recent years as an important inflammation mediator, playing a prominent role in the pathogenesis of various types of malignant neoplasm. MIF is a glycoprotein that presents a wide spectrum of biological activities and exerts a complex interaction with various cellular signaling pathways, causing imbalance of homeostasis. Experimental and clinical studies show that high levels of MIF are found in almost all types of human cancers and are implicated in seemingly all stages of development of the tumors. The production of MIF is triggered through an autocrine signal emitted by tumor cells, and stimulates the production of cytokines, chemokines, and growth as well as angiogenic factors that lead to growth of the tumor, increasing its aggressiveness and metastatic potential. MIF is produced by virtually all types of human body cells, in response to stress caused by different factors, leading to pathological conditions such as chronic inflammation and immunomodulation with suppression of immune surveillance and of immune response against tumors, angiogenesis, and carcinogenesis. In this review, we present recent advances on the biological activity of MIF, the signaling pathways with which it is involved and their role in tumorigenesis.

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

“…As already reported MIF is an inflammatory cytokine involved in a large number of cellular pathways, including the control of apoptosis [86]. During the invasive progression of breast cancer, MIF appears involved in the phenomena of trans-endothelial cells migration, related to the intra-and extra-vasation processes [87].…”

“…The expression of this protein stimulates the production of cytokines, chemokines, and growth factors, as well as angiogenic factors, that favour the tumor growth also potentiating its aggressivenes and metastatic spreading [86,87]. The overexpression of MIF has been demonstrated in breast cancer cells, in which, through the interaction with HSP90 and CXCR-4, MIF induces resistance to the apoptosis and stimulates the proliferation via AKT pathway [87].…”

New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations

“…This finding attributes an unusual role of tumor-suppressor to the MMP9, which deserves further attention. Macrophage Migration Inhibitory Factor, MIF (MIF) is an interesting small protein (approximately 12.5 kDa) involved in several biological activities, among which, the stimulation of the production of cytokines, chemokines, growth factors and angiogenic factors, that may favour tumor growth and metastatic spreading [31][32][33]. The overexpression of MIF in breast cancer cells, and its reported interaction with HSP90 and CXCR-4, known to induce resistance to the apoptosis and stimulation of the proliferation via AKT pathway [33], opens new scenery regarding the possible correlations between matrix degradation and cell proliferation.…”

“…Moreover, MIF is involved in the innate immune response and in regulating the function of macrophages in host defense. [32]. Heat Shock 70 kDa Protein 4, HSP74 (HSPA4) and Heat Shock 27kDa Protein, (HSP27) (HSPB1) are two significant members of the multigenic heat shock protein family [34].…”

Toll-like Receptors Regulate MIF Expression in Benign Lymphoepithelial Lesion of the Lacrimal Gland

“…Recently, our team showed that the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is overexpressed in the plasma of BLEL patients [4], however, the causes of this deregulated expression remained unclear. MIF is a pleiotropic pro-inflammatory cytokine implicated in the pathogenesis of several inflammatory disorders, autoimmune diseases and tumors [5][6][7]. MIF is synthesized and stored in the cytoplasm of many cells [8,9] and is released in response to various stimuli including Toll-like receptors (TLRs) engagement with their specific ligands [10].…”