Macrophage inhibitory cytokine-1 in cancer: Beyond the cellular phenotype

Abstract

Despite technological advances in diagnostic abilities and improved treatment methods, the burden of cancers remains high, leading to significant morbidity and mortality. One primary reason is that cancer cell secretory factors modulate the tumor microenvironment, supporting tumor growth and circumvents anticancer activities of conventional therapies. Macrophage inhibitory cytokine-1 (MIC-1) is a pleiotropic cytokine elevated in various cancers. MIC-1 regulates various cancer hallmarks, including sustained proliferation, tumor-promoting inflammation, avoiding immune destruction, inducing invasion, metastasis, angiogenesis, and resisting cell death. Despite these facts, the molecular regulation and downstream signaling of MIC-1 in cancer remain elusive, partly because its receptor (GFRAL) was unknown until recently. Binding of MIC-1 to GFRAL recruits the coreceptor tyrosine kinase RET to execute its downstream signaling. So far, studies have shown that GFRAL expression is restricted to the brain stem and is responsible for MIC-1/GFRAL/RET-mediated metabolic disorders. Nevertheless, abundant levels of MIC-1 expression have been reported in all cancer types and have been proposed as a surrogate biomarker. Given the ubiquitous expression of MIC-1 in cancers, it is crucial to understand both upstream regulation and downstream MIC-1/GFRAL/RET signaling in cancer hallmark traits.

Keywords: Cancer; Cancer hallmarks; Immunosurveillance; MIC-1/GFRAL/RET signaling; Surrogate biomarker.

Figure 1:

Genomic regulation of Macrophage inhibitory cytokine-1 (MIC-1) in cancer cells. Evidence from the literature suggests that various factors induce MIC-1 in a context-dependent manner.

Figure 2:

Macrophage inhibitory cytokine-1 (MIC-1) mediated cellular effects. MIC-1 association with cancer hallmarks traits through various biological features. The categories were masked (given in grey) where it lacks scientific evidence. The illustration were recreated based on a recent review by Hanahan [23].

Figure 3:

A schematic representation of the Macrophage inhibitory cytokine-1 (MIC-1) signaling pathway in cell proliferation. MIC-1 has been shown to have dualistic regulation of MIC-1 signaling. The protumor function of MIC-1 is shown mainly through the activation of ERK and AKT in cancer cells and the antitumor function is mainly through p53-dependent and independent mechanisms..

Figure 4:

Autocrine and paracrine effects of Macrophage inhibitory cytokine-1 (MIC-1) in cancer cell invasion and metastasis. Tumor cell-derived MIC-1 could induce autocrine action at the primary tumor site and paracrine action in tumor microenvironment and in metastasis.

Figure 5:

Macrophage inhibitory cytokine-1 (MIC-1) mediated action on endothelial cells. Under normoxic conditions, MIC-1, possibly through GFRAL, induces CCN2 and inhibits αVβ3 integrin clusteringand prevent endothelial cell proliferation. In hypoxic conditions, MIC-1 could inhibit P53 which then stabilizes the HIF-1α and induces VEGF expression.