PROLIFERATIVE RESPONSES OF THE SKIN TO EXTERNAL STIMULI

The skin, in particular the epidermis, offers unique opportunities to investigate the induction and control of cellular proliferation and ti ssue homeostasis both under in vivo and in vitro conditions. Moreover, it represents one of the most feasible model systems for experimental cancer research. As the primary border of the body, the skin has impo rtant protective and defensive functions. A general response to extern al injury consists of a thickening of the epithelial layer (epidermal hyperplasia) combined with an inflammatory reaction. This hyperplastic transformation of the skin is a critical condition of skin tumor deve lopment (i.e., conversion and promotion) and of the wound response. It is believed to be due to a transformation of keratinocytes into an ac tivated state characterized by an increased rate of proliferation and the ability to release a series of growth factors and other cytokines that coordinate the defense reaction (e.g., hyperproliferation, recrui tment of leukocytes, activation of the immune system) along auto- and paracrine feedback loops. The initial and probably later phases of thi s response depend critically on a local release of eicosanoids such as prostaglandins and lipoxygenase-generated factors. A unique reaction seen upon phorbol ester treatment of mouse skin is a strong induction of the enzyme 8-lipoxygenase, which might be involved in skin tumor de velopment by catalyzing the generation of clastogenic metabolites thou ght to play a role in the conversion stage. Hyperplasia may be conside red to be the result of an imbalance between the rates of cell gain an d cell loss. Therefore, hyperplastic transformation has to be distingu ished from another response of skin to external stimuli where the home ostatic equilibrium is maintained (i.e., no hyperplasia develops in sp ite of strong hyperproliferation). This balanced hyperproliferation as induced by mild stimuli (pressure, phorbol ester 4-O-methyl-TPA) is n either accompanied by inflammatory reactions nor by the symptoms of ke ratinocyte activation. It may simply be due to an increased rate of ce ll-cycle traverse in the proliferative tissue compartment. In contrast , the prostaglandin-dependent activation of keratinocytes leading to h yperplastic transformation resembles in many aspects (such as, for ins tance, the activation of cell -cycle-related genes) the G(o)-S transit ion of cells in vitro. The control of proliferative homeostasis in nor mal epidermis is an unresolved problem. It is not known whether the ra te of cell proliferation adapts automatically to the rate of terminal differentiation or whether this adaption is regulated by local factors such as the elusive chalones or other inhibitory signals like transfo rming growth factor beta. The same is true for stimulatory growth fact ors such as epidermal growth factor and transform ing growth factor-al pha whose function may be that of wound hormones rather than of homeos tatic regulators of normal tissue regeneration.