Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma
Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma
复制标题
单核细胞/巨噬细胞通过 ERK 通路促进肝细胞癌中血管 CXCR4 的表达
DOI：
10.1080/2162402x.2017.1408745
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
Meng, Ya-Ming;Liang, Jing;Zheng, Limin
我们最近发现CXCR 4是一种新的肝细胞癌（HCC）组织血管出芽的血管标记物。因此，CXCR 4+内皮细胞（EC）可以作为可能受益于索拉非尼治疗的患者的潜在预测因子;然而，在HCC中调节血管CXCR 4表达的机制在很大程度上仍然未知。在此，我们揭示了大量的单核细胞/巨噬细胞（Mo/Mφ）选择性地富集在HCC样品中CXCR 4+血管的血管周围区域。用氯化钆（GdCl 3）或唑来膦酸（ZA）处理Mo/Mφ显著降低HCC肿瘤中血管CXCR 4的表达。这种现象也在CCR 2-KO小鼠中得到证实，其表现出肿瘤组织中炎性Mo/Mφ的浸润减少。机制研究表明，肿瘤条件Mo/Mφ产生的炎性细胞因子，尤其是TNF-α，可上调EC上CXCR 4的表达。TNF-α诱导的Raf-ERK通路的激活，而不是Notch信号传导，负责CXCR 4的表达。此外，索拉非尼与ZA的组合治疗通过显著降低血管CXCR 4表达而与改善的抗肿瘤功效相关。这些结果表明Mo/Mφ可以调节肿瘤血管中CXCR 4的表达。因此，抑制Mo/Mφ炎症可能增强索拉非尼在HCC中的治疗效果。
ABSTRACT We recently identified CXCR4 as a novel vascular marker for vessel sprouting in hepatocellular carcinoma (HCC) tissues. Thus, CXCR4+ endothelial cells (ECs) could serve as a potential predictor for patients who may benefit from sorafenib treatment; however, the mechanism that regulates vascular CXCR4 expression in HCC remains largely unknown. Here, we revealed a large number of monocytes/macrophages (Mo/Mφ) to be selectively enriched in the perivascular areas of CXCR4+ vessels in HCC samples. The depletion of Mo/Mφ with gadolinium chloride (GdCl3) or zoledronic acid (ZA) treatment significantly reduced vascular CXCR4 expression in HCC tumors. This phenomenon was also confirmed in CCR2-KO mice, which exhibited reduced infiltration of inflammatory Mo/Mφ in tumor tissues. Mechanistic studies revealed that inflammatory cytokines derived from tumor conditioned Mo/Mφ, especially TNF-α, could up-regulate CXCR4 expression on ECs. TNF-α-induced activation of the Raf-ERK pathway, but not Notch signaling, was responsible for the expression of CXCR4. Moreover, the combination treatment of sorafenib with ZA was associated with improved anti-tumor efficacy by significantly reducing vascular CXCR4 expression. These findings revealed that Mo/Mφ could regulate CXCR4 expression in the tumor vasculature. Thus, the inhibition of Mo/Mφ inflammation might enhance the treatment efficacy of sorafenib in HCC.