title: Co-operation between follicular ornithine decarboxylase and v-Ha-ras induces spontaneous papillomas and malignant conversion in transgenic skin.
abstract: 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.
authors.affiliation: Lankenau Medical Research Center, Wynnewood, PA 19096, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Smith
authors.forename: C S
authors.initials: CS
authors.lastname: Trempus
authors.forename: S K
authors.initials: SK
authors.lastname: Gilmour
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002273:Carcinogens; D000518:Eflornithine / Q000627:therapeutic use; D011905:Genes, ras / Q000502:physiology*; D007636:Keratoacanthoma / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012871:Skin Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D015127:9,10-Dimethyl-1,2-benzanthracene; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D000518:Eflornithine