Origin, Evolution, and Regulation of Cancer Genes: An Overview

Abstract

Cancer is a disease of living cells in the multicellular organisms. Its origins are closely associated with the evolution of multicellularity, which emerged billions of years ago. The “incipient cancer genes” (proto-oncogenes) presumably evolved from cell reproduction genes during the evolutionary transition from unicellular to multicellular organisms. Although initially these incipient cancer genes were involved in rapid cell division required for growth at specific developmental stages, their activity had to be regulated for a balanced growth and differentiation during evolution. Those genes that accomplish the necessary regulation and restraint of potentially cancer-inducing genes, so-called tumor genes (Tu) or cellular oncogenes (c-onc), are the tumor suppressor genes (TS). Cancer is a multistep process, involving a number of genes. In this review, human cancer is considered in the framework of a two-phase genetic model of carcinogenesis consisting of initiation and development. In the two-phase model, the initiation phase may require up to two, or at the most a few genetic changes (gene mutations or chromosomal abnormalities); this phase is potentially irreversible. The developmental phase may involve two or more genetic and/or epigenetic changes. If it consists of epigenetic changes, the developmental phase is potentially reversible. In this model the sites of genetic or epigenetic changes are the TS-genes that are specific for a given tissue or cell type. The number of such regulatory tumor suppressor genes (TS-genes) may be different for different tissues. Diverse environmental factors, such as chemical carcinogens, ionizing radiation, and viruses, acting singly or in combination, may affect the function of the TS-genes either directly or indirectly through mutational or epigenetic effects, thereby resulting in initiation/development of cancer. This model accounts for hereditary as well as sporadic human cancers. Spontaneous or induced regression or reversal of tumor cells to normal state may be centred on the developmental phase of carcinogenesis. In this review, I propose that the origin of cancer genes is part of the evolutionary history of multicellular organisms.