Interferon-α/β and Anti-Fibroblast Growth Factor Receptor 1 Monoclonal Antibody Suppress Hepatic Cancer Cells In Vitro and In Vivo

Shigeru Sasaki,Hideyasu Takagi,Minoru Toyota,Kohzoh Imai,Masahiro Maeda,Masayuki Tsujisaki,Tsutomu Seito,Akinobu Ota,Yasuhisa Shinomura,Tadao Ishida,Hiromu Suzuki,Hiroyuki Yamamoto,Hiroshi Yasui,Akinori Takaoka,Young Nyun Park

doi:10.1371/journal.pone.0019618

Abstract

BackgroundHepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC.Methodology/Principal FindingsWe used Western blot and flow cytometric and immunocytochemical analyses to investigate the regulation of FGFR1 expression by interferon-α/β in several human hepatic cancer cell lines. In addition, we tested the efficacy of combined treatment with anti-FGFR1 monoclonal antibody and interferon-α/β in a murine xenograft model of human HCC. We found that interferon-α/β induces expression of FGFR1 in human HCC cell lines, and that an anti-FGFR1 monoclonal antibody (mAb) targeting of the induced FGFR1 can effectively inhibit growth and survival of HCC cells in vitro and in vivo. Moreover, the combination of interferon-α, anti-FGFR1 mAb and peripheral blood mononuclear cells (PBMCs) exerted a significant antitumor effect in vitro.ConclusionsOur results suggest that the combined use of an anti-FGFR1 antibody and interferon-α/β is a promising approach to the treatment of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide [1]
Our results suggest that the combined use of an anti-fibroblast growth factor receptor 1 (FGFR1) antibody and interferon-a/b is a promising approach to the treatment of HCC
To identify genes up-regulated by IFN in HCC cells, we performed a microarray analysis using cDNA prepared from tumors grown in severe combined immunodeficient (SCID) mice subcutaneously administrated HepG2 cells, a human hepatic cancer cell line

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide [1]. Surgery, percutaneous therapies such as ethanol injection and radiofrequency ablation, and transcatheter therapies such as arterial chemoembolization are employed in the treatment of HCC. These approaches can selectively remove and kill cancer cells, which makes them useful for control of the local tumor; they are not sufficient to improve the prognosis of HCC patients, as the disease readily recurs due to blood-born metastases (e.g., intrahepatic metastasis and vascular infiltration) or the development of new HCCs (multicentric carcinogenesis). Effective therapeutic options available for HCC are limited; the prognosis for these patients is poor.

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