抄録
Background: Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver. Methods: We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses. Results: The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC. Conclusion: Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
| 元の言語 | 英語 |
|---|---|
| ページ（範囲） | 1007-1018 |
| ページ数 | 12 |
| ジャーナル | Journal of gastroenterology |
| 巻 | 54 |
| 発行部数 | 11 |
| DOI | |
| 出版物ステータス | 出版済み - 11 1 2019 |
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All Science Journal Classification (ASJC) codes
- Gastroenterology
これを引用
Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma. / Mano, Yohei; Yoshio, Sachiyo; Shoji, Hirotaka; Tomonari, Shimagaki; Aoki, Yoshihiko; Aoyanagi, Nobuyoshi; Okamoto, Toru; Matsuura, Yoshiharu; Osawa, Yosuke; Kimura, Kiminori; Yugawa, Kyohei; Wang, Huanlin; Oda, Yoshinao; Yoshizumi, Tomoharu; Maehara, Yoshihiko; Kanto, Tatsuya.
：: Journal of gastroenterology, 巻 54, 番号 11, 01.11.2019, p. 1007-1018.研究成果: ジャーナルへの寄稿 › 記事
}
TY - JOUR
T1 - Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma
AU - Mano, Yohei
AU - Yoshio, Sachiyo
AU - Shoji, Hirotaka
AU - Tomonari, Shimagaki
AU - Aoki, Yoshihiko
AU - Aoyanagi, Nobuyoshi
AU - Okamoto, Toru
AU - Matsuura, Yoshiharu
AU - Osawa, Yosuke
AU - Kimura, Kiminori
AU - Yugawa, Kyohei
AU - Wang, Huanlin
AU - Oda, Yoshinao
AU - Yoshizumi, Tomoharu
AU - Maehara, Yoshihiko
AU - Kanto, Tatsuya
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Background: Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver. Methods: We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses. Results: The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC. Conclusion: Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
AB - Background: Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver. Methods: We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses. Results: The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC. Conclusion: Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
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UR - http://www.scopus.com/inward/citedby.url?scp=85064206953&partnerID=8YFLogxK
U2 - 10.1007/s00535-019-01579-5
DO - 10.1007/s00535-019-01579-5
M3 - Article
C2 - 30941514
AN - SCOPUS:85064206953
VL - 54
SP - 1007
EP - 1018
JO - Journal of Gastroenterology
JF - Journal of Gastroenterology
SN - 0944-1174
IS - 11
ER -