We previously revealed the crucial roles of a chemokine, CX3CL1, and its receptor, CX3CR1, in skin wound healing. Although repeated wounds frequently develop into skin cancer, the roles of CX3CL1 in skin carcinogenesis remain elusive. Here, we proved that CX3CL1 protein expression and CX3CR1⁺ macrophages were observed in human skin cancer tissues. Similarly, we observed the enhancement of CX3CL1 expression and the abundant accumulation of CX3CR1⁺ tumor-associated macrophages with M2-like phenotypes in the skin carcinogenesis process induced by the combined treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. In this mouse skin carcinogenesis process, CX3CR1⁺ tumor-associated macrophages exhibited M2-like phenotypes with the expression of Wnt3a and angiogenic molecules including VEGF and matrix metalloproteinase 9. Compared with wild-type mice, CX3CR1-deficient mice showed fewer numbers of skin tumors with a lower incidence. Concomitantly, M2-macrophage numbers and neovascularization were reduced with the depressed expression of angiogenic factors and Wnt3a. Thus, the CX3CL1-CX3CR1 axis can crucially contribute to skin carcinogenesis by regulating the accumulation and functions of tumor-associated macrophages. Thus, this axis can be a good target for preventing and/or treating skin cancers.

我们先前揭示了趋化因子CX3CL1及其受体CX3CR1在皮肤伤口愈合中的关键作用。尽管反复的伤口经常发展为皮肤癌，但是CX3CL1在皮肤癌变中的作用仍然难以捉摸。在这里，我们证明了在人皮肤癌组织中观察到了CX3CL1蛋白表达和CX3CR1 ⁺巨噬细胞。同样地，我们观察到CX3CL1表达和CX3CR1的丰富积累的增强⁺肿瘤相关巨噬细胞与M2状与7,12-二甲基苯并[a]蒽和12-诱导的联合治疗的皮肤癌变过程的表型ø -十四烷酰基佛波醇13-乙酸盐。在此小鼠皮肤癌变过程中，CX3CR1 ⁺与肿瘤相关的巨噬细胞表现出M2型表型，并具有Wnt3a和血管生成分子（包括VEGF和基质金属蛋白酶9）的表达。与野生型小鼠相比，CX3CR1缺陷型小鼠表现出较少的皮肤肿瘤发生率。同时，随着血管生成因子和Wnt3a表达的降低，M2巨噬细胞数量和新生血管减少。因此，CX3CL1-CX3CR1轴可以通过调节肿瘤相关巨噬细胞的积累和功能来关键地促进皮肤癌变。因此，该轴可以成为预防和/或治疗皮肤癌的良好靶标。