Chemerin and Cancer

Abstract

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin's main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin's role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients' survival.

Keywords: adipokine; cancer; chemerin; leukocyte.

Figure 1

Anti-tumoral and cancer-promoting effects of chemerin. Anti-tumoral activities of chemerin, which are dominant in most cancer entities, include inhibition of MAPK, β-catenin and AKT where the latter is achieved by PTEN activation. These actions partially are mediated via the β2-arrestin and RhoA/serum response factor induced signaling. Both pathways are activated by chemerin binding to GPR1 and CMKLR1. In contrast, tumor-promoting effects are mediated by activation of matrix metalloproteinases, MAPK, p38 and AKT with involvement of β-arrestin-1. Angiogenesis is partly enhanced via these pathways. In about ¾ of the tumor types tested, chemerin expression is reduced in cancer tissue when compared to non-tumorous tissues, whereas in about ¼ of cancer entities chemerin expression is elevated. Insulin resistance, inflammation and adipogenesis are influenced by chemerin and may also contribute to tumor growth. Impact of these factors was not studied in detail so far.

Figure 2

Kaplan–Meier diagrams showing the relapse-free survival (RFS) of 3951 breast cancer patients depending on expression of chemerin and its receptors CMKLR, GPR1 and CCRL2 in tumor tissue, based on a metaanalysis of DNA microarray data (http://kmplot.com/analysis/) [64].

Figure 3

Kaplan–Meier diagrams showing the overall survival (OS) of 1656 ovarian cancer patients depending on expression of chemerin and its receptors CMKLR1, GPR1 and CCRL2 in tumor tissue, based on a metaanalysis of DNA microarray data (http://kmplot.com/analysis/) [71].

Figure 4

Kaplan–Meier diagrams showing the overall survival (OS) of 1926 patients with non-small-cell lung cancer (NSCLC) depending on expression of chemerin and its receptors CMKLR1, GPR1 and CCRL2 in NSCLC tissue, based on a metaanalysis of DNA microarray data (http://kmplot.com/analysis/) [76].

Figure 5

Kaplan–Meier diagrams showing the overall survival (OS) of 876 patients with gastric cancer depending on expression of chemerin and its receptors CMKLR1, GPR1 and CCRL2 in gastric cancer tissue, based on a metaanalysis of DNA microarray data (http://kmplot.com/analysis/) [80].

Figure 6

Kaplan–Meier diagrams showing the overall survival (OS) of 364 patients with hepatocellular carcinoma (HCC) depending on expression of chemerin and its receptors CMKLR1, GPR1 and CCRL2 in tumor tissue, based on a metaanalysis of DNA microarray data (http://kmplot.com/analysis/) [83].