THE MALIGNANT CAPACITY OF SKIN TUMORS INDUCED BY EXPRESSION OF A MUTANT H-RAS TRANSGENE DEPENDS ON THE CELL-TYPE TARGETED

Background: Pinpointing the cells from which tumours arise is a major challenge in tumour biology. Previous work has shown that the targeted expression of a mutant ras gene within the interfollicular cell compa rtment of mouse skin induces the formation of benign papillomas, but t hese do not spontaneously progress to malignancy. We have investigated the carcinogenic effects of expressing the same oncogene in a differe nt population of epidermal cells. Results: Expression of mutant ras fr om a truncated keratin 5 gene promoter, which directs expression to th e follicular and interfollicular cells of newborn mice and the hair fo llicle cells of adults, stimulated the development of acanthotic areas in newborn mice. Within one week of birth, the acanthotic skin develo ped areas of carcinoma in situ and adult mice developed papillomas and keratoacanthomas, the latter having a high frequency of spontaneous m alignant transformation to squamous and occasionally spindle carcinoma s. The benign tumours that arose had several hallmarks of tumours at a high risk of malignant progression, including suprabasal cell prolife ration and heterogeneous expression of keratin 13. In contrast to tumo urs induced by expressing mutant ras under the control of the keratin 10 or keratin 1 gene promoters, the formation of these lesions was not dependent on wounding or a tumour promoter, Conclusions: Benign tumou rs that are at a risk of malignant conversion are primarily derived fr om cells located within the hair follicle, and the nature of the cell in which tumour initiation occurs is a major determinant of malignant potential. (C) Current Biology Ltd ISSN 0960-9822.