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Membrane-bound form of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy in a model of hepatocellular carcinoma

Cancer Gene Therapy volume 19, pages 312–319 (2012)Cite this article

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Abstract

Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monocyte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4- and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC.

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Acknowledgements

We thank Mariko Katsuda for assistance with histopathological analysis and immunohistochemistry, and Maki Kawamura and Chiharu Minami for providing animal care.

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Authors and Affiliations

  1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

    Y Marukawa, Y Nakamoto, K Kakinoki, T Tsuchiyama, N Iida, T Kagaya, Y Sakai & S Kaneko

  2. Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medicine, Niigata, Japan

    M Naito

  3. Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    N Mukaida

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  1. Y Marukawa
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  2. Y Nakamoto
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Correspondence to S Kaneko.

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Marukawa, Y., Nakamoto, Y., Kakinoki, K. et al. Membrane-bound form of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy in a model of hepatocellular carcinoma. Cancer Gene Ther 19, 312–319 (2012). https://doi.org/10.1038/cgt.2012.3

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