1. ¹Department of Pediatrics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA
2. ²Department of Surgery, SRU/MSB G482, ML 0558, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA

Correspondence: SE Waltz, E-mail: susan.waltz@uc.edu

Received 5 November 2003; Revised 26 July 2004; Accepted 27 September 2004; Published online 8 November 2004.

Abstract

Recent studies demonstrate that the receptor tyrosine kinase (TK) Ron is tumorigenic when overexpressed and plays a role in regulating skin homeostasis. We hypothesized that Ron signaling promotes skin carcinogenesis. To test this hypothesis, mice deficient in the TK domain of Ron (TK^-/- mice) were crossed with v-Ha-ras (Tg.AC) transgenic mice; the resulting TK^-/- Tg.AC^+/- mice, and their controls, were utilized in a model of chemically induced Ras-mediated skin carcinogenesis. The mice were treated with 2.5 g of 12-O-tetradecanoylphorbol-13-acetate applied weekly to the shaved back of 36 control (TK^+/+ Tg.AC^+/-) and 35 experimental (TK^-/- Tg.AC^+/-) mice. In an analysis of the resulting papillomas, a reduction in cellular proliferation and papilloma volume was found in the TK^-/- Tg.AC^+/- mice compared to controls. Further, Ron protein expression was upregulated during papilloma formation. Ablation of Ron signaling resulted in partial defects in MAPK and Akt signaling that may account for the decreased papilloma growth in the TK^-/- Tg.AC^+/- mice. The papilloma-bearing mice were monitored for the occurrence of malignant skin tumors and other malignant tumor types for a period of 48 weeks. Loss of Ron receptor signaling significantly reduced the percent of papillomas that underwent malignant conversion as well as the number of mice developing other malignant tumor types. In conclusion, these studies demonstrate that Ron signaling augments papilloma growth and malignant conversion in vivo.