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

• Published in: Gene therapy Vol. 7; no. 22; pp. 1906 - 1914
• Main Authors: Endo, S, Zeng, Q, Burke, N A, He, Y, Melhem, M F, Watkins, S F, Lango, M N, Drenning, S D, Huang, L, Rubin Grandis, J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-11-2000
• Subjects: Animals; Antisense therapy; Antitumor activity; Apoptosis; Autocrine signalling; Carcinoma, Squamous Cell - therapy; Cell Division; Cell Line; Cell proliferation; Cytoplasm; Epithelial cells; Gene Expression; Gene therapy; Genetic Therapy - methods; Head & neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - therapy; Humans; Inoculation; Kinases; Mice; Mice, Nude; Microscopy, Fluorescence; mRNA; Mucosa; Neoplasms, Experimental - therapy; Oligonucleotides, Antisense - administration & dosage; Random Allocation; Signal transduction; Squamous cell carcinoma; TGF-^a gene; Transfection - methods; Transforming Growth Factor alpha - genetics; Transforming growth factor-a; Tumor cells; tumor necrosis factor-a; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301315

Unlike normal mucosal squamous epithelial cells, head and neck squamous cell carcinomas (HNSCCs) overexpress TGF-alpha mRNA and protein which is required to sustain the proliferation of HNSCC cells in vitro. To determine whether TGF-alpha expression contributes to tumor growth in vivo, cationic liposome-mediated gene transfer was used to deliver an antisense expression construct targeting the human TGF-alpha gene into human head and neck tumor cells, grown as subcutaneous xenografts in nude mice. The TGF-alpha 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-alpha 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-alpha was accompanied by increased apoptosis in vivo. These experiments indicate that interference with the TGF-alpha/EGFR autocrine signaling pathway may be an effective therapeutic strategy for cancers which overexpress this ligand/receptor pair.