Published online before print June 4, 2009

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(American Journal of Pathology. 2009;175:392-399.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090036

RasGRP1 Transgenic Mice Develop Cutaneous Squamous Cell Carcinomas in Response to Skin Wounding

Potential Role of Granulocyte Colony-Stimulating Factor

Federico R. Diez^*, Ann A. Garrido^*, Amrish Sharma^*, Courtney T. Luke^*, James C. Stone, Nancy A. Dower, J. Mark Cline and Patricia S. Lorenzo^*

From the Natural Products and Cancer Biology Program,^* Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii; the Departments of Biochemistry, and Pediatrics, University of Alberta, Edmonton, Canada; and the Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Models of epidermal carcinogenesis have demonstrated that Ras is a critical molecule involved in tumor initiation and progression. Previously, we have shown that RasGRP1 increases the susceptibility of mice to skin tumorigenesis when overexpressed in the epidermis by a transgenic approach, related to its ability to activate Ras. Moreover, RasGRP1 transgenic mice develop spontaneous papillomas and cutaneous squamous cell carcinomas, some of which appear to originate in sites of injury, suggesting that RasGRP1 may be responding to signals generated during the wound-healing process. In this study, we examined the response of the RasGRP1 transgenic animals to full-thickness incision wounding of the skin, and demonstrated that they respond by developing tumors along the wounded site. The tumors did not present mutations in the H-ras gene, but Rasgrp1 transgene dosage correlated with tumor susceptibility and size. Analysis of serum cytokines showed increased levels of granulocyte colony-stimulating factor in transgenic animals after wounding. Furthermore, in vitro experiments with primary keratinocytes showed that granulocyte colony-stimulating factor stimulated Ras activation, although RasGRP1 was dispensable for this effect. Since granulocyte colony-stimulating factor has been recently associated with proliferation of skin cancer cells, our results may help in the elucidation of pathways that activate Ras in the epidermis during tumorigenesis in the absence of oncogenic ras mutations.