Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

Abstract

Activated ras genes have been frequently identified in both benign and malignant human tumors , including keratoacanthoma and squamous cell carcinoma. In this study , we developed two lines of transgenic rabbits in which the expression of EJras has been specifically targeted to the rabbit epidermal keratinocytes , using the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1 transgenic progenies developed multiple keratoacanthomas at about 3 days after birth. The rabbits developed an average of 20 tumors , which usually reached the size of approximately 1 cm in diameter and then spontaneously regressed in about 2 months , similar to keratoacanthoma regression in humans. In addition , up to 18% of the rabbits then developed squamous cell carcinoma at about 5 months of age. The expression of EJras was detectable in all of the keratoacanthomas and squamous cell carcinomas. These results strongly support the involvement of the ras oncogene in both the initiation and regression of keratoacanthoma , and in the development of squamous cell carcinomas. These novel transgenic rabbits , with their consistent tumorigenic phenotype at an early age , high similarity to the human lesions, and easy accessibility for examination , manipulation, biopsy , and treatment , should provide a unique model system for studying ras activation-related tumor initiation , regression , and progression , and for evaluating antitumor therapies. (Am J Pathol 1999, 155:315-324)Ras genes encode a family of plasma membrane-bound proteins (p21ras) that function as intermediates in cell signal transduction pathways. These proteins play a pivotal role in regulating cell growth and differentiation in nearly all studied eukaryotic cell types. 1 The activity of ras proteins as regulating switches is strictly controlled by cycling between active GTP-bound and inactive GDPbound states. 2 The active and inactive cycling of the p21ras proteins may be broken because of a point mutation at position 12, 13, or 61 of the proteins, which has been found in both experimental and spontaneous tumors. This cellular transformation property is considered to be due to the extended life and resultant accumulation of p21ras proteins in the active GTP state, 3 which leads to tumorigenesis due to loss of regulatory control of cell proliferation and differentiation. However, many aspects of ras mutation-related neoplasia still remain to be elucidated, especially the dual roles of activated ras genes in cell growth stimulation or differentiation, and its correlation with tumor initiation, regression, and progression.It is well known that carcinogenesis is a complex multistep process that usually involves mutation and/or inappropriate expression of certain cellular genes, such as the mutational activation of proto-oncogenes and the inactivation of tumor suppressor genes. Among the oncogenes, activated ras genes have been found in a wide variety of human tumors, and ranges from 10 -20% Haras activation in bladder carcinomas to 85-100% Ki-ras in colorec...

Dietary N-acetyl-L-cysteine modulates benzo[a]pyrene-induced skin tumors in cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) mice

“…The expression of ras was limited to areas of neoplasia as expected (29) and not expressed in surrounding tissue (35). Expression of ras in benign keratoacanthomas appeared more intense than in squamous cell carcinomas and spindle cell tumors, which is consistent with the observations of others (36,37).…”

Ras proteins in the control of the cell cycle and cell differentiation

“…Moreover, mutated H-ras transcripts are up to threefold more abundant than the nonmutated H-ras mRNA [252]. In line with these findings, transgenic rabbits in which the expression of H-RasV12 has been targeted to keratinocytes has recently been shown to develop multiple keratoacanthomas that regress spontaneously [253]. Together, these findings indicate that oncogenic Ras expression in skin cells is compatible with keratinocyte differentiation.…”

An HLA-A2.1-Transgenic Rabbit Model to Study Immunity to Papillomavirus Infection

“…The procedures for producing transgenic rabbits have been previously described (25). In brief, microinjection of the DNA construct HLA-A2.1 (3 g/ml) into the pronucleus of fertilized eggs was conducted.…”