Abstract

Background

Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs.

Methods

Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination.

Results

LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival.

Conclusions

CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.

中文翻译：

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CX3CR1信号在胶质瘤恶性转化中的作用

 抽象的

 背景

趋化因子信号传导可能通过改变肿瘤行为或影响肿瘤微环境来促进低级别胶质瘤 (LGG) 的进展。在本研究中，我们研究了 CX3C 趋化因子受体 1 (CX3CR1) 信号在 LGG 恶性转化中的作用。

 方法

对 90 名 LGG 患者进行了常见CX3CR1 V249I 多态性的基因分型，并检查了生存、基因表达和肿瘤微环境的基因型依赖性改变。利用基因工程小鼠模型来模拟内源性颅内神经胶质瘤，并单独或组合靶向表达 CX3C 配体 1 (CX3CL1) 和 CX3CR1。

 结果

CX3CR1 V249I 多态性杂合子（V/I； n = 43）或纯合子（I/I； n = 2）的 LGG 患者总体中位值显着改善（14.8 vs 9.8 年， P < 0.05）且无进展与野生型基因型 (V/V; n = 45) 相比，存活率 (8.6 vs 6.5 年， P < 0.05)。 V/I + I/I 组的肿瘤表现出CCL2和MMP9转录物水平显着降低，与瘤内 M2 巨噬细胞浸润和微血管密度减少相关。在免疫功能正常的 LGG 小鼠模型中，CX3CL1 和 CX3CR1 的共表达促进了更恶性的肿瘤表型，其特征是小胶质细胞/巨噬细胞浸润和微血管密度增加，导致生存期缩短。

 结论

CX3CR1 V249I 多态性与 LGG 总体生存率和无进展生存率的改善相关。 CX3CR1 信号传导增强肿瘤相关小胶质细胞/巨噬细胞的积累和恶性转化过程中的血管生成。