EPIDERMAL STEM CELLS IN TWO-STAGE CARCINOGENESIS

There are three important characteristics of murine two-stage carcinogenesis: initiation is essentially irreversible; it is latent in the absence of promotion; the tumor responses are similar no matter when promotion is begun - all this in a tissue that undergoes lifelong turnover. Virtually nothing is known about the cells that receive and maintain this "latent" neoplastic lesion". Conceivable, any proliferative epidermal cell could be at risk, but most of the data are consistent with the suggestion that it is the stem cells which actually become the initiated cells. The overall goal of this proposed investigation is to identify and characterize the epidermal stem cells and determine their role in two-stage carcinogenesis. Our hypothesis is that the initiated cells are clonogenic epidermal stem cells which: 1) remain constant in number over time following initiation, 2) increase in number in response to promotion, and 3) have greater proliferative potential in initiated epidermis that in normal epidermis. The specific goals of this investigation are to: 1. identify and characterize the stem cells among the other proliferative keratinocytes of normal murine epidermis according to the paradigm established by work in the bone marrow system; 2. determine how initiation in vivo alters the number and proliferative potential of the clonogenic cells as a function of initiating dosage and interval following exposure; 3. determine the effects of promoting and poorly promoting hyperplastic treatments in vivo on the number and proliferative potential of the clonogenic cells from normal or carcinogen-exposed mice as a function of number of treatments and the time interval following exposure. Not only will the results of these experiments increase our understanding of the role of the epidermal stem cells, they will identify the target populations for chemical carcinogens and tumor promoters. These results should have far reaching consequences for research in skin carcinogenesis, for dermatology, and for understanding the pathobiology of proliferation and differentiation in continually renewing tissues in general.