Cancer-associated fibroblast-derived extracellular vesicles facilitate metastasis in hepatocellular carcinoma by delivering CTGF.

IF 4.8 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2025-07-01 DOI:10.1007/s13402-025-01085-2

Mengli Zheng, Luyao Liu, Haochen Cui, Yuchong Zhao, Wei Chen, Shuya Bai, Wang Peng, Yun Wang, Yanling Li, Ronghua Wang, Xiju Wang, Bin Cheng

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引用次数: 0

Abstract

Purpose: The tumor microenvironment (TME) plays a crucial role in cancer progression. Cancer-associated fibroblasts (CAFs) are key components of the TME and play critical roles in tumor development and metastasis. However, the mechanisms by which CAFs influence hepatocellular carcinoma (HCC) metastasis are not fully understood.

Methods: Extracellular vesicles (EVs) from CAFs and normal fibroblasts (NFs) were characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. An iTRAQ-based proteomic sequencing analysis was conducted to quantify proteins in the EVs from these cells. Colony formation assays and Transwell assays were used to assess tumor cell proliferation and migration. Xenograft tumor models were established in nude mice to evaluate tumor progression in vivo. Coimmunoprecipitation and molecular docking were performed to explore the interactions between CTGF and Notch1.

Results: A high CAF abundance is associated with poor prognosis in HCC patients. EVs from CAFs significantly enhanced the proliferative and invasive abilities of HCC cells in vitro and in vivo. Connective tissue growth factor (CTGF) was found to be highly upregulated in CAF-derived EVs, and CTGF knockdown in CAF-derived EVs attenuated their tumor-promoting capacities. Mechanistically, CTGF derived from CAF-EVs activated the Notch1/Snail1 signaling pathway in recipient cells via interaction with the Notch1 receptor, enhancing HCC cell proliferation and invasion. Furthermore, high CTGF expression was significantly correlated with poor clinicopathological features in HCC patients.

Conclusion: Our findings revealed that CTGF derived from CAF-EVs promoted the proliferation and invasion of HCC cells via activation of the Notch1/Snail1 pathway, highlighting CTGF derived from CAF-EVs as a prognostic biomarker and therapeutic target in HCC.

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癌症相关成纤维细胞来源的细胞外囊泡通过传递CTGF促进肝癌转移。

目的：肿瘤微环境（tumor microenvironment， TME）在肿瘤进展中起着至关重要的作用。癌症相关成纤维细胞（CAFs）是TME的关键组成部分，在肿瘤的发展和转移中起着关键作用。然而，CAFs影响肝细胞癌（HCC）转移的机制尚不完全清楚。方法：采用western blotting、透射电镜和纳米颗粒跟踪分析对CAFs和正常成纤维细胞的细胞外囊泡（EVs）进行表征。通过基于itraq的蛋白质组学测序分析，对来自这些细胞的ev中的蛋白质进行量化。采用菌落形成试验和Transwell试验评估肿瘤细胞的增殖和迁移。在裸鼠身上建立异种移植肿瘤模型，以评估肿瘤在体内的进展。通过共免疫沉淀和分子对接，探索CTGF与Notch1之间的相互作用。结果：高CAF丰度与HCC患者预后不良相关。体外和体内实验中，来自CAFs的ev显著增强了HCC细胞的增殖和侵袭能力。结缔组织生长因子（结缔组织生长因子，CTGF）在caff源性ev中被发现高度上调，CTGF在caff源性ev中被敲低会减弱其促肿瘤能力。机制上，源自cafe - ev的CTGF通过与Notch1受体相互作用激活受体细胞中的Notch1/Snail1信号通路，增强HCC细胞的增殖和侵袭。此外，CTGF高表达与HCC患者较差的临床病理特征显著相关。结论：我们的研究结果表明，来自caf - ev的CTGF通过激活Notch1/Snail1通路促进HCC细胞的增殖和侵袭，突出了来自caf - ev的CTGF在HCC中的预后生物标志物和治疗靶点。

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

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.