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Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

Cancer Gene Therapy volume 12, pages 757–768 (2005)Cite this article

Abstract

We have created a novel cellular vehicle for gene therapy of malignant gliomas by transfection of murine bone marrow stroma cells (MSCs) with a cDNA encoding epidermal growth factor receptor (EGFR). These cells (EGFR-MSCs) demonstrate enhanced migratory responses toward glioma-conditioned media in comparison to primary MSCs in vitro. Enhanced migration of EGFR-MSC was at least partially dependent on EGF-EGFR, PI3-, MAP kinase kinase, and MAP kinases, protein kinase C, and actin polymerization. Unlike primary MSCs, EGFR-MSCs were resistant to FasL-mediated cytotoxicity and were capable of stimulating allogeneic mixed lymphocyte reaction, suggesting EGFR-MSCs possess suitable characteristics as vehicles for brain tumor immuno-gene therapy. Following injection at various sites, including the contralateral hemisphere in the brain of syngeneic mice, EGFR-MSCs were able to migrate toward GL261 gliomas or B16 melanoma in vivo. Finally, intratumoral injection with EGFR-MSC adenovirally engineered to secrete interferon-α to intracranial GL261 resulted in significantly prolonged survival in comparison to controls. These data indicate that EGFR-MSCs may serve as attractive vehicles for infiltrating brain malignancies such as malignant gliomas.

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Acknowledgements

This work was supported by P01 NS40923 (IFP, SCW, HO) and a grant from the Copeland Fund of the Pittsburgh Foundation (HO). We thank Dr Manabu Hatano for helpful discussions in the review of this manuscript.

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Author notes

  1. Hidemitsu Sato and Naruo Kuwashima: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Hidemitsu Sato, Naruo Kuwashima, Tsukasa Sakaida, Manabu Hatano, Jill E Dusak, Wendy K Fellows-Mayle, Ian F Pollack & Hideho Okada

  2. Department of Cell Biology and Physiology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA

    Glenn D Papworth & Simon C Watkins

  3. Department of Surgery and the Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Andrea Gambotto & Hideho Okada

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Correspondence to Hideho Okada.

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Sato, H., Kuwashima, N., Sakaida, T. et al. Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors. Cancer Gene Ther 12, 757–768 (2005). https://doi.org/10.1038/sj.cgt.7700827

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