Mutations, evolution and the central role of a self-defined fitness function in the initiation and progression of cancer

Abstract

The origin and progression of cancer is widely viewed as "somatic evolution" driven by the accumulation of random genetic changes. This theoretical model, however, neglects fundamental conditions for evolution by natural selection, which include competition for survival and a local environmental context. Recent observations that the mutational burden in different cancers can vary by 2 orders of magnitude and that multiple mutations, some of which are "oncogenic," are observed in normal tissue suggests these neglected Darwinian dynamics may play a critical role in modifying the evolutionary consequences of molecular events. Here we discuss evolutionary principles in normal tissue focusing on the dynamical tension between different evolutionary levels of selection. Normal somatic cells within metazoans do not ordinarily evolve because their survival and proliferation are governed by tissue signals and internal controls (e.g. telomere shortening) that maintain homeostatic function. The fitness of each cell is, thus, identical to the whole organism, which is the evolutionary level of selection. For a cell to evolve, it must acquire a self-defined fitness function so that its survival and proliferation is determined entirely by its own heritable phenotypic properties. Cells can develop independence from normal tissue control through randomly accumulating mutations that disrupt its ability to recognize or respond to all host signals. A self-defined fitness function can also be gained non-genetically when tissue control signals are lost due to injury, inflammation, or infection. Accumulating mutations in cells without a self-defined fitness function will produce no evolution - consistent with reports showing mutations, including some that would ordinarily be oncogenic, are present in cells from normal tissue. Furthermore, once evolution begins, Darwinian forces will promote mutations that increase fitness and eliminate those that do not. Thus, cancer cells will typically have a mutational burden similar to adjacent normal cells and many (perhaps most) mutations observed in cancer cells occurred prior to somatic evolution and may not contribute to the cell's malignant phenotype. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.

Keywords: Cancer evolution somatic mutations theory; Fitness function; Somatic evolution.

Figure 1

A normal epithelial cell (left) is non-evolving because its survival and proliferation are entirely governed by tissue controls acting though intracellular pathways. Somatic evolution toward cancer requires a self-defined fitness function meaning that the cell’s survival and proliferation are determined by its own heritable phenotypic properties. One route to a self-defined fitness function (right) is the accumulation of random mutations which cumulatively turn off the cell’s reception or response to tissue messages. A second pathway (center) is loss of tissue signal due to inflammation, wounding, or infection. In this case, cells within the tissue are rendered independent and have an opportunity to evolve so that any prior mutations are suddenly relevant to its survival and proliferation. This cell now can potentially evolve toward a cancer phenotype before the tissue recovers and restores normal control signals.