Early events in the neoplastic transformation of respiratory epithelium

The complex process of epithelial carcinogenesis is composed of discrete biologic events including the early activation events of "initiation" and "promotion." For lung cancer, these events are only now being elucidated. Despite the identification of possible target genes and their mutations, the "initiation" events for lung cancer remain poorly understood. The identification of these "initiation" events is a crucial step toward the development of practical molecular markers for early detection of this disease. The reversible process of tumor promotion remains somewhat enigmatic but is a promising target for chemoprevention. A wide range of substances, including asbestos and various substances in cigarette smoke, behave as tumor promoters for lung cancer. They appear to promote tumor formation by inducing cellular proliferation mediated in part by growth factors. The intracellular signals these factors provide are ultimately translated into cellular growth via steps involving nuclear transcription factors. Early response genes such as the jun and fos gene family members encode such nuclear transcription factors which are expressed in lung cancer cells and primary bronchial epithelial cells. The expression of these transcription factors is highly responsive to stimulation by growth factors including serum, transforming growth factor, and gastrin-releasing peptide. A more thorough understanding of this process will allow the development of molecular and/or pharmacologic antagonists that can interfere with the biologic process of tumor promotion and therefore function as chemoprevention agents.