Integrating genetic and nongenetic drivers of somatic evolution during carcinogenesis: The biplane model

Abstract

The multistep transition from a normal to a malignant cellular phenotype is often termed “somatic evolution” caused by accumulating random mutations. Here, we propose an alternative model in which the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host. However, these mutations are not carcinogenic because normal cells in multicellular organism cannot ordinarily evolve. That is, proliferation and death of normal cells are controlled by local tissue constraints typically governed by nongenomic information dynamics in the cell membrane. As a result, the cells of a multicellular organism have a fitness that is identical to the host, which is then the unit of natural selection. Somatic evolution of a cell can occur only when its fate becomes independent of host constraints. Now, survival, proliferation, and death of individual cells are dependent on Darwinian dynamics. This cellular transition from host‐defined fitness to self‐defined fitness may, consistent with the conventional view of carcinogenesis, result from mutations that render the cell insensitive to host controls. However, an identical state will result when surrounding tissue cannot exert control because of injury, inflammation, aging, or infection. Here, all surviving cells within the site of tissue damage default to self‐defined fitness functions allowing them to evolve so that the mutations accumulated over the lifetime of the host now serve as the genetic heritage of an evolutionary unit of selection. Furthermore, tissue injury generates a new ecology cytokines and growth factors that might promote proliferation in cells with prior receptor mutations. This model integrates genetic and nongenetic dynamics into cancer development and is consistent with both clinical observations and prior experiments that divided carcinogenesis to initiation, promotion, and progression steps.

Ecology of Fear: Spines, Armor and Noxious Chemicals Deter Predators in Cancer and in Nature

“…We see cancer as a speciation event in which a protist evolves from the cells of its host (Gatenby and Brown, 2017;Gatenby et al, 2020;Pienta et al, 2020a). From this perspective, microorganisms provide the closest examples for cancer of armored, spiny, and noxious defenses, both in form and function.…”

A Similar Speciation Process Relying on Cellular Stochasticity in Microbial and Cancer Cell Populations

“…Recently, Gatenby et al. proposed a novel hypothesis for carcinogenesis that integrates genetic and non-genetic drivers of somatic evolution ( Gatenby et al., 2020 ). Although the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host, they propose that this tumorigenesis starts only when cells carrying these oncogenic mutations are in an environment promoting their proliferation ( Gatenby et al., 2020 ).…”

“…proposed a novel hypothesis for carcinogenesis that integrates genetic and non-genetic drivers of somatic evolution ( Gatenby et al., 2020 ). Although the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host, they propose that this tumorigenesis starts only when cells carrying these oncogenic mutations are in an environment promoting their proliferation ( Gatenby et al., 2020 ). Indeed, most of the time cells, even when they harbor oncogenic mutations, remain under control by local tissue constraints ( Martincorena et al., 2015 ; Yizhak et al., 2019 ; Yokoyama et al., 2019 ), being also involved in the cooperative functioning that governs the multicellular host as the unit of natural selection.…”

Insights From the Ecology of Information to Cancer Control

“…The reaction norm of normal cells is tightly controlled on a tissue level in a way that response to microenvironmental cues is within the fitness function of a tissue/whole organism. 27 In contrast, the fate of cancer cells is determined by the interactions of their phenotypic properties with the local microenvironment. Here, the cells must specifically not receive and/or process local tissue instructions.…”