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TGF-α antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo

Gene Therapy volume 7, pages 1906–1914 (2000)Cite this article

Abstract

Unlike normal mucosal squamous epithelial cells, head and neck squamous cell carcinomas (HNSCCs) overexpress TGF-α mRNA and protein which is required to sustain the proliferation of HNSCC cells in vitro. To determine whether TGF-α expression contributes to tumor growth in vivo, cationic liposome-mediated gene transfer was used to deliver an antisense expression construct targeting the human TGF-α gene into human head and neck tumor cells, grown as subcutaneous xenografts in nude mice. The TGF-α antisense gene was immediately detected in the cytoplasm of the tumor cells, translocated to the nucleus by 12 h and remained localized to the nucleus for up to 3 days. Direct inoculation of the TGF-α antisense (but not the corresponding sense) construct into established HNSCC tumors resulted in inhibition of tumor growth. Sustained antitumor effects were observed for up to 1 year after the treatments were discontinued. Down-modulation of TGF-α was accompanied by increased apoptosis in vivo. These experiments indicate that interference with the TGF-α/EGFR autocrine signaling pathway may be an effective therapeutic strategy for cancers which overexpress this ligand/receptor pair.

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Acknowledgements

We are grateful to Dr Reuben Lotan for the gift of the cell line 1483. This work was supported in part by Public Health Service grants CA01760, CA72526, and CA77038 from The National Cancer Institute (to JRG), The Eye and Ear Foundation, The Pittsburgh Foundation, The Mary Hillman Jennings Foundation and the Veterans Research Foundation of Pittsburgh.

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Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    S Endo, Q Zeng, M N Lango, S D Drenning & J Rubin Grandis

  2. Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    N A Burke, S F Watkins & J Rubin Grandis

  3. Department of Pharmacology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Y He & L Huang

  4. Department of Pathology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    M F Melhem

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Endo, S., Zeng, Q., Burke, N. et al. TGF-α antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo. Gene Ther 7, 1906–1914 (2000). https://doi.org/10.1038/sj.gt.3301315

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Keywords

  • transforming growth factor alpha
  • head and neck cancer

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