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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.

journal_name

Evol Appl

journal_title

Evolutionary applications

authors

Gatenby RA,Avdieiev S,Tsai KY,Brown JS

doi

10.1111/eva.12973

subject

Has Abstract

pub_date

2020-05-13 00:00:00

pages

1651-1659

issue

issn

1752-4571

pii

EVA12973

journal_volume

pub_type

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