Response modification in carcinogenesis.

A major goal in multistep carcinogenesis research is the integration of recent findings obtained by sophisticated molecular-genetic and cytogenetic analysis of cancer into the more descriptive concepts of experimental pathology. It is proposed that the creation of a promotable cell in carcinogenic initiation requires a response modification to extracellular or intercellular signals. Different types of response modification can be distinguished: changes in the receptors for growth and differentiation factors and their cytoplasmic and nuclear signal transduction pathways; increased resistance of initiated cells to cytotoxic agents; alterations in junctional cell-to-cell communications. The challenge of a response-modified cell to an appropriate promoter results in its selection and clonal expansion, usually to a benign tumor. In addition, for malignancy, chromosomal changes are required that affect cellular functions that can play a role early or late in tumorigenesis. These concepts are illustrated with examples from oncogene research and oxidant promotion.