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Therapeutic adenoviral gene transfer of a glycosyltransferase for prevention of peritoneal dissemination and metastasis of gastric cancer

Cancer Gene Therapy volume 21, pages 427–433 (2014)Cite this article

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Abstract

Increased expression of sialyl Lewisx/a carbohydrates, ligands for E-selectin, correlates with clinically advanced stages and metastasis of gastric and colon cancers. In contrast, Sda carbohydrate is abundantly detected in the normal gastrointestinal mucosa but dramatically reduced or lost in cancer tissues. A glycosyltransferase, β1,4N-acetylgalactosaminyltransferase 2 (B4GALNT2) that catalyzes Sda carbohydrate synthesis, is silenced in cancer. In the present study, we aimed at reducing the expression of sialyl Lewisx/a of cancer cells in vivo by forced expression of B4GALNT2 and Sda, thereby preventing dissemination/metastasis, especially metastasis triggered by surgical maneuvers. We used a fiber-modified adenovirus (Ad) vector that contained a chimeric construct with a serotype 5 shaft and a serotype 3 knob. Using this Ad5/3 vector, we successfully introduced the B4GALNT2 gene into a human gastric cancer cell line KATO III in vitro and confirmed replacement of sialyl Lewisx to Sda with a decrease in E-selectin-dependent adhesion. Administration of Ad5/3-B4GALNT2 vectors into the peritoneal cavity of mice after inoculation of KATO III cells with laparotomy significantly reduced the incidence of metastasis. Our results indicate that the transfer of a single gene encoding B4GALNT2 modified carbohydrate chains of cancer cells in vivo and decreased tumor dissemination and metastasis.

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Acknowledgements

We thank Dr Makoto Satoh (Department of Urology, Sen-en Rifu Hospital, Miyagi, Japan) for providing TOS-1 cells, and Ms Miyuki Nakasuji for her technical assistance as well as Dr Yutaka J Kawamura for his helpful advice and discussion. This research was partly supported by grants from the programs Grants-in-Aid for Young Scientists, Grants-in-Aid for Scientific Research (C), Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Cultures, Sports, Science, and Technology, International Cooperation Research Grants from Ministry of Health, Labor, and Welfare and National Center for Global Health and Medicine (21-110, 22-205, 21-129, 25-104). Monoclonal antibodies KM694 and KM93 were both provided from Tokyo Research Park, Kyowa Hakko Kirin, Tokyo, Japan.

Author information

Author notes

  1. Y Adachi

    Present address: 7Current address: Department of Surgery, Takaoka Fushiki Hospital, Takaoka, Japan.,

  2. D T Curiel

    Present address: 8Current address: Department of Radiation Oncology, School of Medicine, Washington University in St Louis, St Louis, MO, USA.,

  3. R Kannagi

    Present address: 9Current address: Department of Molecular Regulation for Intractable Diseases Institute of Medical Science, Advanced Medical Research Center, Aichi Medical University, Aichi, Japan.,

  4. N Nishimoto

    Present address: 10Current address: Tokyo Medical University, Tokyo, Japan.,

Authors and Affiliations

  1. Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan

    Y I Kawamura, R Kawashima & T Dohi

  2. CREST, Japan Science and Technology Agency, Tokyo, Japan

    Y I Kawamura, R Kannagi & T Dohi

  3. Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

    Y Adachi & N Nishimoto

  4. Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Surgery, Pathology, and the Gene Therapy Center at UAB, University of Alabama at Birmingham, Birmingham, AL, USA

    D T Curiel

  5. Department of Biochemistry, School of Allied Health Sciences, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan

    R Kawashima

  6. Program of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan

    R Kannagi

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  1. Y I Kawamura
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Correspondence to T Dohi.

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Kawamura, Y., Adachi, Y., Curiel, D. et al. Therapeutic adenoviral gene transfer of a glycosyltransferase for prevention of peritoneal dissemination and metastasis of gastric cancer. Cancer Gene Ther 21, 427–433 (2014). https://doi.org/10.1038/cgt.2014.46

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  • DOI: https://doi.org/10.1038/cgt.2014.46

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