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C-X-C 趋化因子受体 2 介导的肿瘤细胞与巨噬细胞间的串扰促进胃癌转移。

A C-X-C Chemokine Receptor Type 2-Dominated Cross-talk between Tumor Cells and Macrophages Drives Gastric Cancer Metastasis.

机构信息

Center for Digestive Disease, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.

Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

出版信息

Clin Cancer Res. 2019 Jun 1;25(11):3317-3328. doi: 10.1158/1078-0432.CCR-18-3567. Epub 2019 Feb 22.

DOI:10.1158/1078-0432.CCR-18-3567
PMID:30796034
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8955044/
Abstract

PURPOSE

C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated cross-talk between gastric cancer cells and macrophages still remains unclear. The expression of CXCR2 and its ligands in 155 human gastric cancer tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A coculture system was established, and functional assays, including ELISA, transwell, cell viability assay, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting gastric cancer growth and metastasis. A xenograft gastric cancer model and a lymph node metastasis model were established to study the function of CXCR2 .

RESULTS

CXCR2 expression is associated with the prognosis of patients with gastric cancer ( = 0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of gastric cancer cells. Macrophages are the major sources of CXCL1 and CXCL5 in the gastric cancer microenvironment, and promote migration of gastric cancer cells through activating a CXCR2/STAT3 feed-forward loop. Gastric cancer cells secrete TNF-α to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of gastric cancer cells can suppress migration and metastasis of gastric cancer and .

CONCLUSIONS

Our study suggested a previously uncharacterized mechanism through which gastric cancer cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat gastric cancer.

摘要

目的

C-X-C 趋化因子受体 2（CXCR2）是驱动肿瘤微环境中免疫抑制和炎症的关键调节因子。CXCR2 靶向治疗已在几种实体瘤中显示出良好的效果。然而，CXCR2 介导的胃癌细胞与巨噬细胞之间串扰的潜在机制仍不清楚。通过免疫组织化学分析了 155 个人类胃癌组织中 CXCR2 及其配体的表达，并评估了与临床特征的相关性。建立了共培养系统，并进行了 ELISA、Transwell、细胞活力测定和 qPCR 等功能测定，以确定 CXCR2 信号轴在促进胃癌生长和转移中的作用。建立了异种移植胃癌模型和淋巴结转移模型，以研究 CXCR2 的功能。

结果

CXCR2 的表达与胃癌患者的预后相关（=0.002）。在所有的 CXCR2 配体中，CXCL1 和 CXCL5 可显著促进胃癌细胞的迁移。巨噬细胞是胃癌微环境中 CXCL1 和 CXCL5 的主要来源，通过激活 CXCR2/STAT3 正反馈环促进胃癌细胞的迁移。胃癌细胞分泌 TNF-α诱导巨噬细胞释放 CXCL1 和 CXCL5。抑制胃癌细胞的 CXCR2 途径可以抑制胃癌的迁移和转移。

结论

本研究提出了一个以前未被描述的机制，即胃癌细胞与巨噬细胞相互作用促进肿瘤生长和转移，提示 CXCR2 可能作为治疗胃癌的有前途的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/ef20b6322120/nihms-1522605-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/cd1d9ac6a1ca/nihms-1522605-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/93a658c5ceb2/nihms-1522605-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/bf1936ac3e58/nihms-1522605-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/6164e4b54dac/nihms-1522605-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/357922023068/nihms-1522605-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/ef20b6322120/nihms-1522605-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/cd1d9ac6a1ca/nihms-1522605-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/93a658c5ceb2/nihms-1522605-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/bf1936ac3e58/nihms-1522605-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/6164e4b54dac/nihms-1522605-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/357922023068/nihms-1522605-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca47/8955044/ef20b6322120/nihms-1522605-f0006.jpg

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