New dimensions in the biology of cancer

A common thread interwoven throughout the literature of cancer biology is a wide‐ranging abnormality of gene regulation, manifested by misprogramming of protein synthesis. This phenomenon encompasses virtually every means of identification of proteins, including antigens, hormones, growth factors, membrane components, and enzymes. Studies by the author and others of the activities of enzymes existing in multiple forms (termed isozymes) in a series of rat hepatomas ranging widely in growth rate, degree of differentiation, and other phenotypic properties has extended this concept and added to it a dimension of functional significance. Isozymes that are in high activity in adult liver and that are geared kinetically to catalyze specific hepatic functions are lost in varying degrees and generally depend on the growth rate and degree of differentiation. In fast growing, poorly differentiated hepatomas, these are replaced by high activities of isozymes that are normally low or absent in adult liver. In many instances, the isozymes that are expressed in poorly differentiated hepatomas are present also in fetal liver, thus pointing to reactivation of genes that were active in the fetus but were inactivated during normal embryonic development. The loss of isozymes that are under rigid host endocrine control, as well as other proteins that maintain the differentiated state, and the re‐activation of genes coding for fetal or ectopic proteins are probably crucial factors in the initiation and maintenance of cellular proliferation.