Ephrin A1 Stimulates CCL2 Secretion to Facilitate Pre-metastatic Niche Formation and Promote Gastric Cancer Liver Metastasis

IF 12.5 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2024-10-16 DOI:10.1158/0008-5472.can-24-1254

Yun Cui, Yongxia Chang, Xixi Ma, Meng Sun, Yuliang Huang, Feng Yang, Shuang Li, Wei Zhuo, Wei Liu, Bo Yang, Aifu Lin, Guangshuo Ou, Yuehong Yang, Shanshan Xie, Tianhua Zhou

{"title":"Ephrin A1 Stimulates CCL2 Secretion to Facilitate Pre-metastatic Niche Formation and Promote Gastric Cancer Liver Metastasis","authors":"Yun Cui, Yongxia Chang, Xixi Ma, Meng Sun, Yuliang Huang, Feng Yang, Shuang Li, Wei Zhuo, Wei Liu, Bo Yang, Aifu Lin, Guangshuo Ou, Yuehong Yang, Shanshan Xie, Tianhua Zhou","doi":"10.1158/0008-5472.can-24-1254","DOIUrl":null,"url":null,"abstract":"The liver is a primary target for distal metastasis of gastric cancer (GC). The hepatic pre-metastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in GC could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in GC cells significantly increased CCL2 secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStCs) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in GC cells. Moreover, high CCL2 expression correlated with poor survival in GC patients. Overall, these findings reveal that EFNA1 signaling in GC cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic pre-metastatic niche that supports liver metastasis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/0008-5472.can-24-1254","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

The liver is a primary target for distal metastasis of gastric cancer (GC). The hepatic pre-metastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in GC could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in GC cells significantly increased CCL2 secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStCs) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in GC cells. Moreover, high CCL2 expression correlated with poor survival in GC patients. Overall, these findings reveal that EFNA1 signaling in GC cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic pre-metastatic niche that supports liver metastasis.

查看原文本刊更多论文

Ephrin A1刺激CCL2分泌，促进转移前龛位形成并促进胃癌肝转移

肝脏是胃癌（GC）远端转移的主要目标。肝转移前生态位（PMN）促进了原发肿瘤和肝脏之间的重要沟通，因此在肝转移中发挥着至关重要的作用。鉴定驱动肝转移龛形成的分子机制有助于制定预防和治疗肝转移的策略。在这里，我们发现了ephrin A1（EFNA1）信号在PMN形成过程中的作用。GC 细胞中 EFNA1 的过表达通过 Hippo-YAP 通路显著增加了 CCL2 的分泌。分泌的 CCL2 通过 WNT/β-catenin 通路激活肝 PMN 中的肝星状细胞（HStCs）。抑制CCL2能明显抑制HStC的活化，减少GC细胞中由EFNA1信号传导引发的肝转移。此外，CCL2的高表达与GC患者的不良生存率相关。总之，这些研究结果表明，GC 细胞中的 EFNA1 信号可上调 CCL2，从而激活 HStC，建立支持肝转移的肝转移前生态位。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.