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TGF alpha is dispensable for skin tumorigenesis in Tg.AC mice
M C Humble1, C J Szczesniak, N C Luetteke
1Curriculum in Toxicology, University of North Carolina, Chapel Hill 27514, USA.
Abstract:
Alterations in growth factor signaling pathways frequently accompany the development and maintenance of epithelial neoplasia. Transforming growth factor alpha (TGF alpha) and its epidermal growth factor receptor have been thought to play an especially important role in epithelial neoplasia. In this study, mice were derived genetically deficient (null) in functional TGF alpha expression and carrying the Tg.AC/v-Ha-ras transgene. The goals were to determine if (a) papillomagenesis was dependent on TGF alpha and (b) progression to malignancy was dependent on TGF alpha expression. Groups of male and female mice heterozygous or homozygous for the TGF alpha null allele and hemizygous for the Tg.AC transgene were treated twice weekly for 10 or 15 wk with doses of 12-O-tetradecanoylphorbol-13-acetate (TPA) known to produce papillomas in Tg.AC mice. Papillomas were readily induced in both male and female TGF alpha null mice. Malignant progression of papillomas was observed in all TGF alpha null treatment groups. Additionally, we examined the response of TGF alpha null mice to full thickness dorsal wounds, a stimulus known to promote papillomagenesis in Tg.AC mice. As in the TPA study, papillomas were induced in both male and female TGF alpha null mice. These studies indicate that TGF alpha is not required for the induction and maintenance of papillomas nor is it essential for the malignant conversion of papillomas in Tg.AC mice.
Insights
Transforming growth factor alpha (TGF alpha) is not essential for the development or malignant progression of skin tumors in mice. These findings challenge the established role of TGF alpha in epithelial neoplasia.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Growth factor signaling pathways are crucial in epithelial neoplasia.
- Transforming growth factor alpha (TGF alpha) and its receptor are implicated in epithelial tumor development.
Purpose of the Study:
- To investigate the necessity of TGF alpha in papillomagenesis.
- To determine if TGF alpha is essential for the progression of papillomas to malignancy.
Main Methods:
- Genetically engineered mice lacking functional TGF alpha (null) were used.
- Mice were crossed with Tg.AC/v-Ha-ras transgene carriers.
- Tumor induction was achieved using 12-O-tetradecanoylphorbol-13-acetate (TPA) or dorsal wounding.
Main Results:
- Papillomas were successfully induced in TGF alpha null mice via TPA treatment and wounding.
- Malignant progression of papillomas occurred in all TGF alpha null treatment groups.
- TGF alpha is not required for papilloma induction, maintenance, or malignant conversion.
Conclusions:
- TGF alpha is dispensable for both the initiation and progression of epithelial neoplasia in this mouse model.
- The study refutes the essential role of TGF alpha in the development and malignancy of epithelial tumors.