Al Delbany Diana, Robert Virginie, Dubois-Vedrenne Ingrid, Del Prete Annalisa, Vernimmen Maxime, Radi Ayoub, Lefort Anne, Libert Frédérick, Wittamer Valérie, Sozzani Silvano, Parmentier Marc
I.R.I.B.H.M and Welbio, Campus Erasme, Université Libre de Bruxelles, 808 Route de Lennik, B-1070 Brussels, Belgium.
Evotec SAS, 195 Route d'Espagne, 31036 Toulouse, France.
Cancers (Basel). 2021 Oct 5;13(19):5000. doi: 10.3390/cancers13195000.
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 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 in tumor cells reversed the consequences of knockout in the host. The phenotypes associated with CCRL2 gain or loss of function were largely abrogated by knocking out the chemerin or 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.
CCRL2属于G蛋白偶联受体家族，是三种chemerin受体之一。它被认为是一种无信号传导功能的受体，将chemerin呈递给表达功能性chemerin受体ChemR23/CMKLR1以及可能的GPR1的细胞。在本研究中，我们探究了CCRL2在小鼠癌症模型中所起的作用。在皮肤致癌化学模型（DMBA/TPA）中，CCRL2功能缺失加速了乳头状瘤的发展，而B16和LLC肿瘤细胞移植瘤的生长则被延迟。当B16和LLC细胞过表达CCRL2时，也观察到肿瘤生长延迟，而肿瘤细胞中CCRL2基因敲除则逆转了宿主中CCRL2基因敲除的后果。与CCRL2功能获得或缺失相关的表型在很大程度上因chemerin或CCRL2基因敲除而消除。携带CCRL2的细胞可以浓缩生物活性chemerin并促进表达CMKLR1的细胞的激活。在表达CCRL2的肿瘤移植瘤中观察到新生血管生成减少，这与表达chemerin的肿瘤表型相似。本研究表明，CCRL2与非典型趋化因子受体（ACKR）家族具有功能相似性。肿瘤细胞对其表达可显著调节chemerin/CMKLR1系统的作用，并作为肿瘤发生的负调节因子。
