Co-operation between follicular ornithine decarboxylase and v-Ha-ras induces spontaneous papillomas and malignant conversion in transgenic skin

• Published in: Carcinogenesis (New York) 1998-08, Vol.19 (8), p.1409-1415
• Main Authors: SMITH, M. K, TREMPUS, C. S, GILMOUR, S. K
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Animal tumors. Experimental tumors; Animals; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinogens; Eflornithine - therapeutic use; Experimental skin tumors; Genes, ras - physiology; Keratoacanthoma - chemically induced; Keratoacanthoma - drug therapy; Keratoacanthoma - genetics; Medical sciences; Mice; Mice, Transgenic; Ornithine Decarboxylase - genetics; Ornithine Decarboxylase - metabolism; Papilloma - chemically induced; Papilloma - drug therapy; Papilloma - genetics; Proliferating Cell Nuclear Antigen - metabolism; Skin Diseases - chemically induced; Skin Diseases - drug therapy; Skin Diseases - genetics; Skin Neoplasms - chemically induced; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Tetradecanoylphorbol Acetate; Tumors
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/19.8.1409

Ornithine decarboxylase (ODC) is aberrantly regulated in tumor cells and results in high basal levels of ODC and polyamines in many epithelial tumors. To determine if elevated ODC/polyamine levels can co-operate with a mutant Ha-ras gene in mouse skin tumorigenesis, double transgenic mice were generated by breeding K6/ODC transgenic mice with TG.AC v-Ha-ras transgenic mice. A K6 keratin promoter drives the ODC transgene in K6/ ODC transgenic mice, which results in elevated ODC/ polyamine levels directed to the outer root sheath cells of hair follicles. TG.AC transgenic mice carry a v-Ha-ras transgene while still retaining two normal c-Ha-ras alleles. Transgenic mice that possess only the K6/ODC or the v-Ha-ras transgene did not develop tumors unless treated with either a carcinogen or a tumor promoter, respectively. However, a high percentage of double transgenic mice possessing both the K6/ODC and v-Ha-ras transgenes developed spontaneous tumors. All tumors were well-differentiated keratoacanthomas, some of which progressed to carcinomas within 2 months. The development and the maintenance of these ODC/ras tumors was ODC-dependent since alpha-difluoromethylornithine (DFMO), a specific ODC inhibitor, prevented the formation and caused the regression of these tumors. These findings indicate that ODC overexpression and an activated Ha-ras are sufficient to produce a high rate of malignant transformation in an animal model. The ODC/ras double transgenic mouse provides a simple in vivo model without the use of chemical carcinogens or tumor promoters in which to test downstream effectors that play a key role in mediating the development of epithelial tumors resulting from the cooperation between ODC and v-Ha-ras.