CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression

Yuki Makino, Hayato Hikita, Takahiro Kodama, Minoru Shigekawa, Ryoko Yamada, Ryotaro Sakamori, Hidetoshi Eguchi, Eiichi Morii, Hideki Yokoi, Masashi Mukoyama, Suemizu Hiroshi, Tomohide Tatsumi, Tetsuo Takehara

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/þ). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/þ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and a-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF ex ression but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody.

Original languageEnglish
Pages (from-to)4902-4914
Number of pages13
JournalCancer Research
Volume78
Issue number17
DOIs
Publication statusPublished - Sep 1 2018

Fingerprint

Connective Tissue Growth Factor
Hepatic Stellate Cells
Hepatocellular Carcinoma
Hep G2 Cells
Liver
Neoplasms
Growth
Antibodies
Hepatocytes
Interleukin-6
Cell Line
Coculture Techniques
Heterografts
Cell Communication

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Makino, Y., Hikita, H., Kodama, T., Shigekawa, M., Yamada, R., Sakamori, R., ... Takehara, T. (2018). CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression. Cancer Research, 78(17), 4902-4914. https://doi.org/10.1158/0008-5472.CAN-17-3844

CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression. / Makino, Yuki; Hikita, Hayato; Kodama, Takahiro; Shigekawa, Minoru; Yamada, Ryoko; Sakamori, Ryotaro; Eguchi, Hidetoshi; Morii, Eiichi; Yokoi, Hideki; Mukoyama, Masashi; Hiroshi, Suemizu; Tatsumi, Tomohide; Takehara, Tetsuo.

In: Cancer Research, Vol. 78, No. 17, 01.09.2018, p. 4902-4914.

Research output: Contribution to journalArticle

Makino, Y, Hikita, H, Kodama, T, Shigekawa, M, Yamada, R, Sakamori, R, Eguchi, H, Morii, E, Yokoi, H, Mukoyama, M, Hiroshi, S, Tatsumi, T & Takehara, T 2018, 'CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression', Cancer Research, vol. 78, no. 17, pp. 4902-4914. https://doi.org/10.1158/0008-5472.CAN-17-3844
Makino, Yuki ; Hikita, Hayato ; Kodama, Takahiro ; Shigekawa, Minoru ; Yamada, Ryoko ; Sakamori, Ryotaro ; Eguchi, Hidetoshi ; Morii, Eiichi ; Yokoi, Hideki ; Mukoyama, Masashi ; Hiroshi, Suemizu ; Tatsumi, Tomohide ; Takehara, Tetsuo. / CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression. In: Cancer Research. 2018 ; Vol. 78, No. 17. pp. 4902-4914.
@article{cd1bbe473d5b4614bac3ac5bbd82bcb9,
title = "CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression",
abstract = "Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/{\th}). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/{\th} CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and a-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF ex ression but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody.",
author = "Yuki Makino and Hayato Hikita and Takahiro Kodama and Minoru Shigekawa and Ryoko Yamada and Ryotaro Sakamori and Hidetoshi Eguchi and Eiichi Morii and Hideki Yokoi and Masashi Mukoyama and Suemizu Hiroshi and Tomohide Tatsumi and Tetsuo Takehara",
year = "2018",
month = "9",
day = "1",
doi = "10.1158/0008-5472.CAN-17-3844",
language = "English",
volume = "78",
pages = "4902--4914",
journal = "Cancer Research",
issn = "0008-5472",
number = "17",

}

TY - JOUR

T1 - CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression

AU - Makino, Yuki

AU - Hikita, Hayato

AU - Kodama, Takahiro

AU - Shigekawa, Minoru

AU - Yamada, Ryoko

AU - Sakamori, Ryotaro

AU - Eguchi, Hidetoshi

AU - Morii, Eiichi

AU - Yokoi, Hideki

AU - Mukoyama, Masashi

AU - Hiroshi, Suemizu

AU - Tatsumi, Tomohide

AU - Takehara, Tetsuo

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/þ). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/þ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and a-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF ex ression but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody.

AB - Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/þ). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/þ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and a-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF ex ression but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody.

UR - http://www.scopus.com/inward/record.url?scp=85052717946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052717946&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-17-3844

DO - 10.1158/0008-5472.CAN-17-3844

M3 - Article

AN - SCOPUS:85052717946

VL - 78

SP - 4902

EP - 4914

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 17

ER -