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肿瘤生态系统中的动态相互作用：肝癌细胞与成纤维细胞之间的通讯。

Dynamic Interplay in Tumor Ecosystems: Communication between Hepatoma Cells and Fibroblasts.

机构信息

Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary.

MS Proteomics Research Group, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary.

出版信息

Int J Mol Sci. 2023 Sep 12;24(18):13996. doi: 10.3390/ijms241813996.

DOI:10.3390/ijms241813996
PMID:37762298
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10530979/
Abstract

Tumors are intricate ecosystems where cancer cells and non-malignant stromal cells, including cancer-associated fibroblasts (CAFs), engage in complex communication. In this study, we investigated the interaction between poorly (HLE) and well-differentiated (HuH7) hepatoma cells and LX2 fibroblasts. We explored various communication channels, including soluble factors, metabolites, extracellular vesicles (EVs), and miRNAs. Co-culture with HLE cells induced LX2 to produce higher levels of laminin β1, type IV collagen, and CD44, with pronounced syndecan-1 shedding. Conversely, in HuH7/LX2 co-culture, fibronectin, thrombospondin-1, type IV collagen, and cell surface syndecan-1 were dominant matrix components. Integrins α6β4 and α6β1 were upregulated in HLE, while α5β1 and αVβ1 were increased in HuH7. HLE-stimulated LX2 produced excess MMP-2 and 9, whereas HuH7-stimulated LX2 produced excess MMP-1. LX2 activated MAPK and Wnt signaling in hepatoma cells, and conversely, hepatoma-derived EVs upregulated MAPK and Wnt in LX2 cells. LX2-derived EVs induced over tenfold upregulation of SPOCK1/testican-1 in hepatoma EV cargo. We also identified liver cancer-specific miRNAs in hepatoma EVs, with potential implications for early diagnosis. In summary, our study reveals tumor type-dependent communication between hepatoma cells and fibroblasts, shedding light on potential implications for tumor progression. However, the clinical relevance of liver cancer-specific miRNAs requires further investigation.

摘要

肿瘤是一个复杂的生态系统，其中癌细胞和非恶性基质细胞（包括癌相关成纤维细胞（CAFs））之间存在复杂的相互作用。在这项研究中，我们研究了低分化（HLE）和高分化（HuH7）肝癌细胞与 LX2 成纤维细胞之间的相互作用。我们探索了多种通讯途径，包括可溶性因子、代谢物、细胞外囊泡（EVs）和 miRNAs。与 HLE 细胞共培养诱导 LX2 产生更高水平的层粘连蛋白 β1、IV 型胶原和 CD44，伴有明显的 syndecan-1 脱落。相反，在 HuH7/LX2 共培养中，纤维连接蛋白、血小板反应蛋白-1、IV 型胶原和细胞表面 syndecan-1 是主要的基质成分。HLE 中整合素 α6β4 和 α6β1 上调，而 HuH7 中 α5β1 和 αVβ1 上调。HLE 刺激的 LX2 产生过量的 MMP-2 和 9，而 HuH7 刺激的 LX2 产生过量的 MMP-1。LX2 激活 MAPK 和 Wnt 信号通路在肝癌细胞中，反之，肝癌衍生的 EVs 上调 LX2 细胞中的 MAPK 和 Wnt。LX2 衍生的 EVs 诱导肝癌 EV 货物中 SPOCK1/testican-1 的十倍以上上调。我们还鉴定了肝癌衍生 EVs 中的肝癌特异性 miRNAs，这可能对早期诊断具有重要意义。总之，我们的研究揭示了肝癌细胞和成纤维细胞之间依赖肿瘤类型的通讯，为肿瘤进展的潜在影响提供了新的认识。然而，肝癌特异性 miRNAs 的临床相关性需要进一步研究。

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