Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth

Makoto Horikawa; Shinichiro Koizumi; Tomoya Oishi; Taisuke Yamamoto; Masashi Ikeno; Masahiko Ito; Tomohiro Yamasaki; Shinji Amano; Tetsuro Sameshima; Yasuyuki Mitani; Yoshihiro Otani; Yuanqing Yan; Tetsuro Suzuki; Hiroki Namba; Kazuhiko Kurozumi

doi:10.1038/s41417-022-00527-5

Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth

Makoto Horikawa, Shinichiro Koizumi, Tomoya Oishi, Taisuke Yamamoto, Masashi Ikeno, Masahiko Ito, Tomohiro Yamasaki, Shinji Amano, Tetsuro Sameshima, Yasuyuki Mitani, Yoshihiro Otani, Yuanqing Yan, Tetsuro Suzuki, Hiroki Namba, Kazuhiko Kurozumi^*

^*Corresponding author for this work

Surgery, Thoracic Surgery Division

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

Original language	English (US)
Pages (from-to)	85-95
Number of pages	11
Journal	Cancer Gene Therapy
Volume	30
Issue number	1
DOIs	https://doi.org/10.1038/s41417-022-00527-5
State	Published - Jan 2023

Funding

This work was supported by Hamamatsu University School of Medicine (HUSM) Grant-in-Aid. This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP20K09325 (KK), JP19K09523 (TS). We thank all members of the laboratory for their discussions and suggestions. Part of this work was performed at the Advanced Research Facilities & Services (ARFS), Hamamatsu University School of Medicine. We also thank Mitchell Arico from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Cancer Research

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10.1038/s41417-022-00527-5

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Horikawa, M., Koizumi, S., Oishi, T., Yamamoto, T., Ikeno, M., Ito, M., Yamasaki, T., Amano, S., Sameshima, T., Mitani, Y., Otani, Y., Yan, Y., Suzuki, T., Namba, H., & Kurozumi, K. (2023). Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth. Cancer Gene Therapy, 30(1), 85-95. https://doi.org/10.1038/s41417-022-00527-5

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title = "Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth",

abstract = "Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.",

author = "Makoto Horikawa and Shinichiro Koizumi and Tomoya Oishi and Taisuke Yamamoto and Masashi Ikeno and Masahiko Ito and Tomohiro Yamasaki and Shinji Amano and Tetsuro Sameshima and Yasuyuki Mitani and Yoshihiro Otani and Yuanqing Yan and Tetsuro Suzuki and Hiroki Namba and Kazuhiko Kurozumi",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jan,

doi = "10.1038/s41417-022-00527-5",

language = "English (US)",

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Horikawa, M, Koizumi, S, Oishi, T, Yamamoto, T, Ikeno, M, Ito, M, Yamasaki, T, Amano, S, Sameshima, T, Mitani, Y, Otani, Y, Yan, Y, Suzuki, T, Namba, H & Kurozumi, K 2023, 'Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth', Cancer Gene Therapy, vol. 30, no. 1, pp. 85-95. https://doi.org/10.1038/s41417-022-00527-5

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T1 - Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth

AU - Horikawa, Makoto

AU - Koizumi, Shinichiro

AU - Oishi, Tomoya

AU - Yamamoto, Taisuke

AU - Ikeno, Masashi

AU - Ito, Masahiko

AU - Yamasaki, Tomohiro

AU - Amano, Shinji

AU - Sameshima, Tetsuro

AU - Mitani, Yasuyuki

AU - Otani, Yoshihiro

AU - Yan, Yuanqing

AU - Suzuki, Tetsuro

AU - Namba, Hiroki

AU - Kurozumi, Kazuhiko

PY - 2023/1

Y1 - 2023/1

N2 - Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

AB - Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

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Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth

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UN SDGs

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