12 Oncogenes and Multistep Carcinogenesis

Abstract

I. INTRODUCTION
The tumors that arise spontaneously in humans and following chemical treatment of experimental animals are formed by a complex, multistep process. This has long been apparent to pathologists who classify tumors on the basis of invasiveness, loss of differentiated traits, and a host of cytological markers. In a number of instances, it has been apparent that tumors composed of benign, relatively differentiated cells represent precursors to more malignant tumors appearing later in the course of tumorigenesis.

Observations of this sort imply a process in which tumor cell populations evolve progressively from cells that deviate only minimally from normalcy toward cells having highly aggressive, invasive behavior (Foulds 1954; Nowell 1976, 1986; Farber 1984). Such change has formal similarities with models in which species change progressively through the processes of Darwinian evolution. According to such thinking, genetic and phenotypic variability in tumor cell populations makes possible the appearance of variants that display phenotypes conferring special growth advantage within a tissue or organism. As such cell clones expand to larger size, they spawn subclones that in turn have acquired yet other novel phenotypes that then drive their own preferential expansion and eventual dominance. Tumor cell populations can thus be seen in constant flux, with new subpopulations continually replacing older ones by virtue of the display of one or another novel, advantageous phenotype.

The advantageous traits exhibited by tumor cell subclones might include increased growth rates, decreased dependency on growth factor stimulation, increased tolerance to anoxia, increased ability to evade immunological defenses,...