Expression of CCRL2 Inhibits Tumor Growth by Concentrating Chemerin and Inhibiting Neoangiogenesis

SIMPLE SUMMARY: Chemerin is a multifunctional protein regulating inflammation, immune responses, and metabolism. It was also shown to display anti-tumoral properties in various cancer models. CMKLR1 is the main functional receptor of chemerin. C-C motif chemokine receptor-like 2 (CCRL2) is another receptor binding chemerin with high affinity but failing to signal through any known signaling pathway. CCRL2 is strongly upregulated by inflammatory signals and was shown to regulate inflammatory reactions in diverse pathological conditions. Expression of CCRL2 was described in many types of human tumors such as melanoma, neuroblastoma, prostate, breast, and gastric cancer. However, its functional role in cancer has not been studied much so far. We investigate in this study how CCRL2 expression can influence the distribution of chemerin and thereby its biological activity in different tumoral contexts. ABSTRACT: CCRL2 belongs to the G protein-coupled receptor family and is one of the three chemerin receptors. It is considered as a non-signaling receptor, presenting chemerin to cells expressing the functional chemerin receptor ChemR23/CMKLR1 and possibly GPR1. In the present work, we investigate the role played by CCRL2 in mouse cancer models. Loss of function of Ccrl2 accelerated the development of papillomas in a chemical model of skin carcinogenesis (DMBA/TPA), whereas the growth of B16 and LLC tumor cell grafts was delayed. Delayed tumor growth was also observed when B16 and LLC cells overexpress CCRL2, while knockout of Ccrl2 in tumor cells reversed the consequences of Ccrl2 knockout in the host. The phenotypes associated with CCRL2 gain or loss of function were largely abrogated by knocking out the chemerin or Cmklr1 genes. Cells harboring CCRL2 could concentrate bioactive chemerin and promote the activation of CMKLR1-expressing cells. A reduction of neoangiogenesis was observed in tumor grafts expressing CCRL2, mimicking the phenotype of chemerin-expressing tumors. This study demonstrates that CCRL2 shares functional similarities with the family of atypical chemokine receptors (ACKRs). Its expression by tumor cells can significantly tune the effects of the chemerin/CMKLR1 system and act as a negative regulator of tumorigenesis.