The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis--thirty-third G. H. A. Clowes Memorial Award Lecture.

The multistage nature of cancer pathogenesis was first defined over 50 years ago by the sequential topical application of chemical agents to mouse skin. Since then, the skin model has provided remarkable insights into the biology, biochemistry, pharmacology, and genetics of carcinogenesis. Discoveries from studies of mouse skin have proved to be landmarks in cancer research including: the binding of carcinogens to DNA; the monoclonal origin of benign and malignant tumors; the powerful tumor-promoting action of phorbol esters; the antipromoting potency of retinoids and steroids; the modifying role of age, caloric intake, and specific dietary constituents on cancer induction; the variable risk for benign tumors to progress to cancer; and the requirement for multiple genetic changes in malignant conversion. Many of these concepts are now widely applied to the interpretation of specific molecular discoveries both in simple experimental systems and in human cancers, but the power of this quantitative, multistage skin carcinogenesis model has made these assessments possible. It has also provided the separation of mechanistically distinct stages in cancer pathogenesis: initiation; promotion; premalignant progression; and malignant conversion. This paper will review our current understanding of the genetic, biological, and biochemical alterations that contribute to the evolution of each of these stages in skin carcinogenesis. These new insights provide an opportunity to replace the traditional operational-based schemata defining the process of carcinogenesis with a working model designed around functional alterations in neoplastic cells.