Keratinocyte stem cells: targets for cutaneous carcinogens

A skin cancer seen in the clinic is in reality the culmination of a long history, only the later stages of which are easily observed. Progression from normal growth to the neoplastic, and later to the metastatic, stage of disease may involve multiple changes in cellular phenotypes and patterns of gene expression. Nonetheless, the early events in the pathway that leads from exposure to mutagenic agents to the formation of skin papillomas or carcinomas can be viewed as a two-step process of tumor initiation and tumor promotion. Fundamental questions remain about this process. In particular, the identity and the biological properties have yet to be defined of those cells, existing within a larger population of basal keratinocytes, that are specifically subject to tumor initiation. In addition, the behavior of these cells before, during, and after tumor promotion remains uncertain. The rare cells in this tissue that are capable of becoming pre-neoplastic when treated with a carcinogen exhibit many of the properties expected of keratinocyte stem cells. Here, I consider the evidence that they are indeed stem cells, and I explore the implications of this hypothesis for carcinogenesis in the skin. Based on the hierarchical stem cell model of cellular replacement — originally described by Gilbert and Lajtha (1, 2) for the hematopoietic bone marrow, and later discussed by Buick (3) and by Hume (4) — a stem cell represents a self-renewing cell that may also produce proliferative cells, which undergo a series of amplification divisions prior to terminal maturation. Stem cells are thought to be quiescent or to cycle slowly under normal circumstances and to be protected by the architecture of the tissue. They should also be capable, when appropriately stimulated, of extensive proliferation to produce terminally differentiated progeny, and they should be capable of self-renewing in vivo and in vitro in order to maintain their own population as well as that of the terminally differentiated cells. Furthermore, some but not all stem cells are multipotential, that is, capable of producing more than one terminally differentiated lineage. Given this definition, do the targets of carcinogen action meet this definition of a stem cell (5)? Keratinocyte stem cells have not yet been isolated, but some of their features are now becoming evident. From work in my laboratory and others, it is now possible to identify subpopulations with varying proliferative potential within the basal layer of the epidermis. This, along with other characteristics, suggests that some of these cells correspond to true stem cells. Keratinocyte subpopulations can be defined by various characteristics — location within the tissue, responses to chemical treatments, mitotic behavior in vivo or in vitro, morphology, and expression of marker proteins. Each of these parameters helps define a subpopulation that may contain stem cells, but none of them, taken individually, provides an accepted operational definition of the keratinocyte stem cell. Together, however, these parameters show great promise for the identification and isolation of keratinocyte stem cells. I will focus on the properties of these candidate stem cell populations and the possible identities among them, as well as on the evidence that these cells are the targets of two-stage carcinogenesis.