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

• Published in: International journal of molecular sciences Vol. 24; no. 18; p. 13996
• Main Authors: Petővári, Gábor, Tóth, Gábor, Turiák, Lilla, L. Kiss, Anna, Pálóczi, Krisztina, Sebestyén, Anna, Pesti, Adrián, Kiss, András, Baghy, Kornélia, Dezső, Katalin, Füle, Tibor, Tátrai, Péter, Kovalszky, Ilona, Reszegi, Andrea
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.09.2023; MDPI
• Subjects: Blood vessels; Cancer; Cell culture; Cell cycle; Collagen; Communication; Cooperation; Cyclin-dependent kinases; Cytokines; Development and progression; Ecosystems; Epigenetics; Fibroblasts; Glycoproteins; Hepatoma; Immune system; Kinases; Liver; Liver cancer; Metabolites; MicroRNA; Phosphorylation; Proteins; Scientific equipment and supplies industry; Signal transduction; Hungary; United States; Massachusetts; Germany
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241813996

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.