Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention

Abstract

Chemerin [RARRES2 [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses—where it can act as both a pro- and anti-inflammatory mediator—the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/RARRES2 in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.

Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

“…Previous studies described low chemerin in human HCC [7]. In murine NASH livers, chemerin protein was highly expressed and was not changed in the tumors [47].…”

“…Reduced chemerin expression and an anti-tumor effect for chemerin have been reported for several forms of cancer [7]. For example, chemerin expression is low in adrenocortical carcinoma and chemerin overexpression in immune-deficient mice reduced tumor growth.…”

Chemerin partly mediates tumor‐inhibitory effect of all‐trans retinoic acid via CMKLR1‐dependent natural killer cell recruitment

“…Although the majority of studies have been focused on the ability of chemerin to modulate tissue inflammation or metabolism, more attention has recently been paid to the role of chemerin in tumor. Clinical studies suggest the correlation of down‐regulated systemic and/or tumoral chemerin expression with the progression of several types of tumor including melanoma, liver cancer and adrenocortical carcinoma . Several mechanisms have been shown to be involved in the tumor‐inhibitory effect of chemerin, including the promotion of anti‐tumor immunity through the recruitment of NK cells or the inhibition of MDSC generation, or direct inhibition of tumor cell growth or migration, depending on the context of tumor.…”

“…Further studies have revealed an anti‐inflammatory role of chemerin in several mouse models of inflammatory disease by reducing the production of inflammatory cytokines and neutrophil infiltration, suggesting a context‐dependent regulatory effect of chemerin on tissue inflammation . A role of chemerin in tumor has recently been recognized . Down‐regulated chemerin expression was detected in most tumor types, including melanoma and liver cancer, and overexpression of chemerin could inhibit tumor growth and metastasis through different mechanisms including direct inhibition of the proliferation and migration of tumor cells or modulation of the tumor microenvironment .…”

“…9,10 A role of chemerin in tumor has recently been recognized. 11 Down-regulated chemerin expression was detected in most tumor types, including melanoma and liver cancer, [11][12][13] and overexpression of chemerin could inhibit tumor growth and metastasis through different mechanisms including direct inhibition of the proliferation and migration of tumor cells or modulation of the tumor microenvironment. [12][13][14][15] For example, our previous study demonstrated that chemerin inhibits the progression of orthotopic murine liver cancer by reducing tumor-promoting inflammation, and others found that chemerin inhibits the invasion of human liver cancer cells.…”