Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma

Yohei Mano, Sachiyo Yoshio, Hirotaka Shoji, Shimagaki Tomonari, Yoshihiko Aoki, Nobuyoshi Aoyanagi, Toru Okamoto, Yoshiharu Matsuura, Yosuke Osawa, Kiminori Kimura, Kyohei Yugawa, Huanlin Wang, Yoshinao Oda, Tomoharu Yoshizumi, Yoshihiko Maehara, Tatsuya Kanto

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Abstract

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.

Original languageEnglish
Pages (from-to)1007-1018
Number of pages12
JournalJournal of gastroenterology
Volume54
Issue number11
DOIs
Publication statusPublished - Nov 1 2019

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Bone Morphogenetic Protein 4
Hepatocellular Carcinoma
Fibroblasts
Phenotype
Liver
Neoplasms
Cancer-Associated Fibroblasts
Cytokines
Tumor Microenvironment
Interleukin-8
Transcriptome
Chemokines
Recombinant Proteins
Interleukin-6
Fibrosis
Tissue Donors

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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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.

In: Journal of gastroenterology, Vol. 54, No. 11, 01.11.2019, p. 1007-1018.

Research output: Contribution to journalArticle

Mano, Y, Yoshio, S, Shoji, H, Tomonari, S, Aoki, Y, Aoyanagi, N, Okamoto, T, Matsuura, Y, Osawa, Y, Kimura, K, Yugawa, K, Wang, H, Oda, Y, Yoshizumi, T, Maehara, Y & Kanto, T 2019, 'Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma', Journal of gastroenterology, vol. 54, no. 11, pp. 1007-1018. https://doi.org/10.1007/s00535-019-01579-5
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. / Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma. In: Journal of gastroenterology. 2019 ; Vol. 54, No. 11. pp. 1007-1018.
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abstract = "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.",
author = "Yohei Mano and Sachiyo Yoshio and Hirotaka Shoji and Shimagaki Tomonari and Yoshihiko Aoki and Nobuyoshi Aoyanagi and Toru Okamoto and Yoshiharu Matsuura and Yosuke Osawa and Kiminori Kimura and Kyohei Yugawa and Huanlin Wang and Yoshinao Oda and Tomoharu Yoshizumi and Yoshihiko Maehara and Tatsuya Kanto",
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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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