TGF-β–independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC
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Yeonhwa Song1,4, Jin-Sun Kim2, Eun Kyung Choi3, Joon Kim4, Kang Mo Kim2, Haeng Ran Seo1
1Cancer Biology Research Laboratory, Institut Pasteur Korea, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13488, Korea
2Division of Gastroenterology and Hepatology, ASAN Medical Center, Seoul, 05505, Korea
3Division of Radiation Oncology, ASAN Medical Center, Seoul, 05505, Korea
4Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, 02841, Korea
Haeng Ran Seo, email: [email protected]
Kang Mo Kim, email: [email protected]
Keywords: tumor spheroids, collagen 1A1, connective tissue growth factor (CTGF), cell adhesion-mediated drug resistance (CAM-DR), hepatocellular carcinoma
Received: April 13, 2016 Accepted: January 29, 2017 Published: February 20, 2017
Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapeutic agents and remains an unmet medical need. Here, we demonstrate a mechanism of cell adhesion-mediated drug resistance using a variety of HCC spheroid models to overcome environment-mediated drug resistance in HCC. We classified spheroids into two groups, tightly compacted and loosely compacted aggregates, based on investigation of dynamics of spheroid formation. Our results show that compactness of HCC spheroids correlated with fibroblast-like characteristics, collagen 1A1 (COL1A1) content, and capacity for chemoresistance. We also showed that ablation of COL1A1 attenuated not only the capacity for compact-spheroid formation, but also chemoresistance. Generally, connective tissue growth factor (CTGF) acts downstream of transforming growth factor (TGF)-β and promotes collagen I fiber deposition in the tumor microenvironment. Importantly, we found that TGF-β–independent CTGF is upregulated and regulates cell adhesion-mediated drug resistance by inducing COL1A1 in tightly compacted HCC spheroids. Furthermore, losartan, which inhibits collagen I synthesis, impaired the compactness of spheroids via disruption of cell-cell contacts and increased the efficacy of anticancer therapeutics in HCC cell line- and HCC patient-derived tumor spheroids. These results strongly suggest functional roles for CTGF-induced collagen I expression in formation of compact spheroids and in evading anticancer therapies in HCC, and suggest that losartan, administered in combination with conventional chemotherapy, might be an effective treatment for liver cancer.
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