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Research Article Free access | 10.1172/JCI111020

Role in nude mice of interferon and natural killer cells in inhibiting the tumorigenicity of human hepatocellular carcinoma cells infected with hepatitis B virus

Daniel Shouval, Bracha Rager-Zisman, Phuc Quan, David A. Shafritz, Barry R. Bloom, and Lola M. Reid

The Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Find articles by Shouval, D. in: JCI | PubMed | Google Scholar

The Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Find articles by Rager-Zisman, B. in: JCI | PubMed | Google Scholar

The Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Find articles by Quan, P. in: JCI | PubMed | Google Scholar

The Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Find articles by Shafritz, D. in: JCI | PubMed | Google Scholar

The Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Find articles by Bloom, B. in: JCI | PubMed | Google Scholar

The Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Find articles by Reid, L. in: JCI | PubMed | Google Scholar

Published August 1, 1983 - More info

Published in Volume 72, Issue 2 on August 1, 1983
J Clin Invest. 1983;72(2):707–717. https://doi.org/10.1172/JCI111020.
© 1983 The American Society for Clinical Investigation
Published August 1, 1983 - Version history
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Abstract

The human hepatoma cell line, PLC/PRF/5, which is persistently infected with hepatitis B virus (HBV), has integrated HBV-DNA, secretes HBV surface antigen (HBsAg), and does not grow readily in congenitally athymic (nu/nu) mice. The present investigation was undertaken to ascertain whether the low tumorigenicity of this cell line was governed by a host immune response and/or was related to expression of HBsAg. Subcutaneous injection of 4-5 X 106 cells into BALB/c nude mice produced localized encapsulated tumors with morphologic features of primary hepatocellular carcinoma in 25% of the animals within 29-40 d. No tumor growth was observed at lower cell inocula. In contrast, SK-HEP-1, an HBV-negative human hepatoma cell line, produced tumors at 1-5 X 106 cells inocula in 66% of the animals. Immunosuppression of mice with antilymphocyte serum (ALS) or irradiation increased tumor incidence in mice inoculated with 1 X 106 PLC/PRF/5 cells to almost 100% and produced local invasiveness. Immunosuppression also reduced the latency, i.e., time to tumor appearance, and increased mean tumor weight. These results suggest that tumorigenicity was limited by the host immune response.

The nature of the response was delineated by treating nude mice challenged with tumor cells with sheep anti-mouse interferon globulin (anti-IFN). When 2 X 106 cells were injected, tumor growth occurred in 75% of anti-IFN-treated mice, whereas controls injected with the same number of cells, but not receiving anti-IFN, failed to develop tumors. The tumors in the anti-IFN-treated mice were highly invasive and the latency period until tumor appearance was reduced to 3-5 d. An inverse correlation was found between susceptibility of the hepatoma cells to natural killer (NK) activity in vitro and resistance to tumor growth in vivo. In vitro cytotoxicity for PLC/PRF/5 cells was eliminated by anti-NK 1.1 and complement, establishing the effector cell as an NK cell. NK cell activity 14 d after inoculation of mice with PLC/PRF/5 cells was augmented against PLC/PRF/5 target cells but not against SK-HEP-1 cells. Treatment of mice with ALS, irradiation, or anti-IFN abolished NK activity against PLC/PRF/5 cells. Co-cultivation of nude mouse spleen cells with PLC/PRF/5 but not with HBsAg or SK-HEP-1 cells induced secretion of murine IFNα. These results suggest that the IFN/NK cell system may play a role in limiting tumorigenicity and invasiveness of HBV-infected human hepatocellular carcinoma cells by a mechanism similar to that found for other cells persistently infected with viruses.

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