Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids

• Published in: Scientific reports Vol. 6; no. 1; p. 36750
• Main Authors: Song, Yeonhwa, Kim, Se-hyuk, Kim, Kang Mo, Choi, Eun Kyung, Kim, Joon, Seo, Haeng Ran
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.11.2016; Nature Publishing Group
• Subjects: 13/109; 14; 14/19; 38; 38/77; 631/67/2329; 631/67/327; 631/80/84; Antibiotics, Antineoplastic - pharmacology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell culture; Cell interactions; Cell Line; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cells, Cultured; Chemoresistance; Chemotherapy; Cisplatin; Collagen (type I); Collagen Type I - genetics; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Endothelial cells; Fibroblasts; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; Multicellular tumor spheroids; multidisciplinary; Science; Spheroids; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stellate cells; Stromal cells; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics
• DOI: 10.1038/srep36750
• ISSN: 2045-2322

Most Hepatocellular carcinoma (HCC) are resistant to conventional chemotherapeutic agents and remain an unmet medical need. Recently, multiple studies on the crosstalk between HCC and their tumor microenvironment have been conducted to overcome chemoresistance in HCC. In this study, we formed multicellular tumor spheroids (MCTS) to elucidate the mechanisms of environment-mediated chemoresistance in HCC. We observed that hepatic stellate cells (HSCs) in MCTS significantly increased the compactness of spheroids and exhibited strong resistance to sorafenib and cisplatin relative to other types of stromal cells. Increased collagen 1A1 (COL1A1) expression was apparent in activated HSCs but not in fibroblasts or vascular endothelial cells in MCTS. Additionally, COL1A1 deficiency, which was increased by co-culture with HSCs, decreased the cell-cell interactions and thereby increased the therapeutic efficacy of anticancer therapies in MCTS. Furthermore, losartan, which can inhibit collagen I synthesis, attenuated the compactness of spheroids and increased the therapeutic efficacy of anticancer therapies in MCTS. Meanwhile, activated HSCs facilitated HCC migration by upregulating matrix metallopeptidase 9 (MMP9) in MCTS. Collectively, crosstalk between HCC cells and HSCs promoted HCC chemoresistance and migration by increasing the expression of COL1A1 and MMP9 in MCTS. Hence, targeting HSCs might represent a promising therapeutic strategy for liver cancer therapy.