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Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy

Cancer Gene Therapy volume 12, pages 954–962 (2005)Cite this article

Abstract

NK4 is an hepatocyte growth factor (HGF)-antagonist and a broad angiogenesis inhibitor. NK4 gene therapy has confirmed antitumor efficacy on cancers with intact HGF-cMET signaling pathway. However, the feasibility to treat tumors in which the effect of the HGF-cMET signaling pathway is less unambiguous or may even be inhibitory on carcinogenesis, such as hepatocellular carcinoma (HCC) with NK4 needs further assessment. Therefore, we evaluated the effects of adenoviral vector-mediated expression of NK4 on the biological behavior of a series of HCC cell lines in vitro and on HepG2 xenografts in vivo. In vitro, transduction of HCC cell lines with the replication-deficient recombinant adenoviral vector AdCMV.NK4 resulted in significant inhibition of proliferation over and above the antimitogenic effects of HGF. In addition, HGF-induced scattering and invasion through matrigel were inhibited effectively. Moreover, transduced HCC cells produced sufficient amounts of NK4 protein to achieve bystander effects involving reduced migration of nontransduced tumor cells and reduced proliferation of endothelial cells. Finally, treatment of established HepG2 xenografts with AdCMV.NK4 resulted in significant tumor growth delay and significant reduction of intratumoral microvessel density. In conclusion, NK4 gene therapy is a promising strategy to treat HCC based on the pleiotropic functions of NK4 interfering with tumor growth, invasion, metastasis and angiogenesis.

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Acknowledgements

We thank Dr K. Matsumoto and Dr T. Nakamura (Osaka University Medical School, Suita, Osaka, Japan) for providing the NK4 cDNA, and Jeroen Mastenbroek and Diederik van den Berg for technical assistance. We thank Elisabeth Bloemena for helping with immunohistochemical examinations and Paul van Diest for help with determination of microvessel density. This work was supported by a research grant from the Pasman Foundation. Renée Overmeer and Daniëlle Heideman are supported by grants from the Dutch Digestive Diseases Foundation (WS02-31 and WS95-12, respectively). Victor van Beusechem is supported by a research fellowship of the Royal Netherlands Academy of Arts and Sciences (KNAW).

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Author notes

  1. Daniëlle A M Heideman and Renée M Overmeer: Authors equally contributed to the paper.

Authors and Affiliations

  1. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    Daniëlle A M Heideman, Peter J F Snijders & Chris J L M Meijer

  2. Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Renée M Overmeer, Victor W van Beusechem & Winald R Gerritsen

  3. AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands

    Wouter H Lamers & Theodorus B M Hakvoort

  4. Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands

    Mikael E Craanen

  5. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

    G Johan A Offerhaus

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  1. Daniëlle A M Heideman
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Correspondence to Daniëlle A M Heideman.

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Heideman, D., Overmeer, R., van Beusechem, V. et al. Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy. Cancer Gene Ther 12, 954–962 (2005). https://doi.org/10.1038/sj.cgt.7700856

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