Exosomal Biglycan promotes gastric cancer progression via M2 polarization and CXCL10-mediated JAK/STAT1 activation

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-04-30 DOI:10.1016/j.canlet.2025.217758

Wenchao Li , Hongfa Wei , Junjie Liu , Zidan Zhao , Fuhui Wang , Liang Qiao , Songcheng Yin , Changhua Zhang , Mingyu Huo

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引用次数: 0

Abstract

Recent advancements in tumor immunotherapy have highlighted the importance of the tumor microenvironment in modulating immune responses against cancer cells. Within the TME, macrophages - particularly the M2 phenotype - serve pivotal regulatory functions through cytokine/chemokine secretion to modulate tumor progression. Elucidating the molecular crosstalk between gastric cancer (GC) cells and tumor-associated macrophages (TAMs) remains imperative for developing targeted therapeutic interventions.

In this study, we identified Biglycan (BGN), a small leucine-rich proteoglycan, as a key mediator in GC progression. Exosomal BGN derived from GC cell is delivered to macrophages, where it binds to NONO protein, thereby driving M2 polarization and upregulating CXCL10 expression. Elevated CXCL10 levels activate the JAK/STAT1 signaling pathways, thereby potentiating GC cell proliferation, invasion, and metastatic dissemination. Clinically, elevated BGN expression correlates with advanced tumor stage and poor prognosis in GC patients, positioning it as a promising therapeutic target.

Our findings reveal a previously unrecognized mechanism of exosomal BGN-mediated M2 macrophage reprogramming and CXCL10-driven oncogenic signaling in the GC microenvironment. These insights establish a novel therapeutic paradigm for GC management through disruption of tumor-macrophage communication.

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外泌体Biglycan通过M2极化和cxcl10介导的JAK/STAT1激活促进胃癌进展

肿瘤免疫治疗的最新进展强调了肿瘤微环境在调节针对癌细胞的免疫反应中的重要性。在TME中，巨噬细胞-特别是M2型-通过细胞因子/趋化因子的分泌来调节肿瘤的进展，发挥关键的调节功能。阐明胃癌（GC）细胞和肿瘤相关巨噬细胞（tam）之间的分子串扰对于开发靶向治疗干预仍然是必要的。在这项研究中，我们确定了Biglycan (BGN)，一种小的富含亮氨酸的蛋白多糖，作为GC进展的关键介质。来自GC细胞的外泌体BGN被递送到巨噬细胞，在巨噬细胞与NONO蛋白结合，从而驱动M2极化，上调CXCL10的表达。CXCL10水平升高激活JAK/STAT1信号通路，从而增强GC细胞的增殖、侵袭和转移传播。在临床上，BGN表达升高与胃癌患者肿瘤分期晚期、预后不良相关，是一个很有前景的治疗靶点。我们的研究结果揭示了GC微环境中外泌体bgn介导的M2巨噬细胞重编程和cxcl10驱动的致癌信号传导的先前未被认识的机制。这些见解为通过破坏肿瘤-巨噬细胞通讯来管理胃癌建立了一种新的治疗范例。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.