i3S, Institute for Research and Innovation in Health, University of Porto, Portugal; INEB, Institute of Biomedical Engineering, University of Porto, Portugal.
CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Cytokine Growth Factor Rev. 2021 Aug;60:107-119. doi: 10.1016/j.cytogfr.2021.03.005. Epub 2021 Mar 31.
Chemokines are essential mediators of immune cell trafficking. In a tumor microenvironment context, chemotactic cytokines are known to regulate the migration, positioning and interaction of different cell subsets with both anti- and pro-tumor functions. Additionally, chemokines have critical roles regarding non-immune cells, highlighting their importance in tumor growth and progression. CCL18 is a primate-specific chemokine produced by macrophages and dendritic cells. This chemokine presents both constitutive and inducible expression. It is mainly associated with a tolerogenic response and involved in maintaining homeostasis of the immune system under physiological conditions. Recently, CCL18 has been noticed as an important component of the complex chemokine system involved in the biology of tumors. This chemokine induces T regulatory cell differentiation and recruitment to the tumor milieu, with subsequent induction of a pro-tumor (M2-like) macrophage phenotype. CCL18 is also directly involved in cancer cell-invasion, migration, epithelial-to-mesenchymal transition and angiogenesis stimulation, pinpointing an important role in the promotion of cancer progression. Interestingly, this chemokine is highly expressed in tumor tissues, particularly at the invasive front of more advanced stages (e.g. colorectal cancer), and high levels are detected in the serum of patients, correlating with poor prognosis. Despite the promising role of CCL18 as a biomarker and/or therapeutic target to hamper disease progression, its pleiotropic functions in a context of cancer are still poorly explored. The scarce knowledge concerning the receptors for this chemokine, together with the insufficient insight on the downstream signaling pathways, have impaired the selection of this molecule as an immediate target for translational research. In this Review, we will discuss recent findings concerning the role of CCL18 in cancer, integrate recently disclosed molecular mechanisms and compile data from current clinical studies.
趋化因子是免疫细胞迁移的重要介质。在肿瘤微环境中，趋化细胞因子被认为调节不同细胞亚群的迁移、定位和相互作用，具有抗肿瘤和促肿瘤功能。此外，趋化因子对于非免疫细胞具有关键作用，突出了它们在肿瘤生长和进展中的重要性。CCL18 是一种灵长类特异性趋化因子，由巨噬细胞和树突状细胞产生。这种趋化因子表现出组成型和诱导型表达。它主要与耐受反应相关，并在生理条件下参与维持免疫系统的稳态。最近，CCL18 已被注意到是参与肿瘤生物学的复杂趋化因子系统的重要组成部分。这种趋化因子诱导 T 调节细胞分化并募集到肿瘤微环境中，随后诱导促肿瘤（M2 样）巨噬细胞表型。CCL18 还直接参与癌细胞侵袭、迁移、上皮-间充质转化和血管生成刺激，在促进癌症进展中起着重要作用。有趣的是，这种趋化因子在肿瘤组织中高度表达，特别是在更晚期（如结直肠癌）的侵袭前沿，并且在患者的血清中检测到高水平，与预后不良相关。尽管 CCL18 作为一种生物标志物和/或治疗靶点来阻碍疾病进展具有很大的潜力，但它在癌症中的多效性功能仍未得到充分探索。该趋化因子的受体知识匮乏，以及对下游信号通路的了解不足，限制了将该分子作为转化研究的直接靶点的选择。在这篇综述中，我们将讨论 CCL18 在癌症中的作用的最新发现，整合最近揭示的分子机制，并汇编来自当前临床研究的数据。
