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 language | English |
|---|---|
| Pages (from-to) | 21650-21662 |
| Number of pages | 13 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - 2017 |
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Keywords
- Cell adhesion-mediated drug resistance (CAM-DR)
- Collagen 1A1
- Connective tissue growth factor (CTGF)
- Hepatocellular carcinoma
- Tumor spheroids
ASJC Scopus subject areas
- Oncology
Cite this
TGF-β-independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC. / Song, Yeonhwa; Kim, Jin Sun; Choi, Eun Kyung; Kim, Joon; Kim, Kang Mo; Seo, Haeng Ran.
In: Oncotarget, Vol. 8, No. 13, 2017, p. 21650-21662.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TGF-β-independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC
AU - Song, Yeonhwa
AU - Kim, Jin Sun
AU - Choi, Eun Kyung
AU - Kim, Joon
AU - Kim, Kang Mo
AU - Seo, Haeng Ran
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Cell adhesion-mediated drug resistance (CAM-DR)
KW - Collagen 1A1
KW - Connective tissue growth factor (CTGF)
KW - Hepatocellular carcinoma
KW - Tumor spheroids
UR - http://www.scopus.com/inward/record.url?scp=85016401260&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016401260&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.15521
DO - 10.18632/oncotarget.15521
M3 - Article
AN - SCOPUS:85016401260
VL - 8
SP - 21650
EP - 21662
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 13
ER -