Foulds' Dangerous Idea Revisited: The Multistep Development of Tumors 40 Years Later

Abstract

The chapter focuses on Fould's analysis of tumor progression. The idea that tumors evolve after a series of mutations that provide the cell with a selective advantage within the gradual process of its emancipation from growth control has attained a dominating position in cancer research, just as Darwinian natural selection is accepted by all biologists. The multistep theory of cancer development originated from two main sources. Mathematical analysis of the age-incidence curves indicated that most of the major human tumors arose after five to seven mutation-like changes. Horizontal studies on the natural history of tumor development at the tissue level, including Foulds' own observations have defined some of these steps in histopathologic and biologic terms. The chapter also discusses oncogenes, tumor suppressor genes, DNA repair genes, and genes that influence programmed cell death by apoptosis. Genetic instability is also an initiating or a contributory factor to many forms of tumor development. Several mutational steps that contribute to the development and progression of colorectal, prostatic, and breast carcinomas and of malignant gliomas are studied at the molecular level. The chapter also discusses multiple step escape mechanism of multistage carcinogenesis.