TGF-β-independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC

Yeonhwa Song, Jin Sun Kim, Eun Kyung Choi, Joon Kim, Kang Mo Kim, Haeng Ran Seo

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 cellcell contacts and increased the efficacy of anticancer therapeutics in HCC cell lineand 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.

Original languageEnglish
Pages (from-to)21650-21662
Number of pages13
JournalOncotarget
Volume8
Issue number13
DOIs
Publication statusPublished - 2017

Keywords

  • Cell adhesion-mediated drug resistance (CAM-DR)
  • Collagen 1A1
  • Connective tissue growth factor (CTGF)
  • Hepatocellular carcinoma
  • Tumor spheroids

ASJC Scopus subject areas

  • Oncology

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