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# Evolutionary dynamics of carcinogenesis and why targeted therapy does not work

## Abstract

All malignant cancers, whether inherited or sporadic, are fundamentally governed by Darwinian dynamics. The process of carcinogenesis requires genetic instability and highly selective local microenvironments, the combination of which promotes somatic evolution. These microenvironmental forces, specifically hypoxia, acidosis and reactive oxygen species, are not only highly selective, but are also able to induce genetic instability. As a result, malignant cancers are dynamically evolving clades of cells living in distinct microhabitats that almost certainly ensure the emergence of therapy-resistant populations. Cytotoxic cancer therapies also impose intense evolutionary selection pressures on the surviving cells and thus increase the evolutionary rate. Importantly, the principles of Darwinian dynamics also embody fundamental principles that can illuminate strategies for the successful management of cancer.

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## Glossary

Atavistic

Reverting to or suggesting the characteristics of a remote ancestor or primitive type. In the current context, atavism is the expression of behaviours in cancer cells that are not normally observed in normal metazoan cells, but that are observed in prokaryotes and/or protozoa.

A taxonomic group of organisms classified together on the basis of homologous features traced to a common ancestor. In the current context, groups of cancer cells evolve in physically distinct niches, and exhibit local genetic homogeneity.

Breast cancers are assessed for the appearance of nuclei within the tumour cells and assigned a grade from 1 (small uniform cells) to 3 (marked nuclear variation).

Supervene

Describes a mathematical and philosophical formalism that characterizes the relationship between two sets — in this case phenotype (or more broadly adaptive strategies) and genotypes. In the subvenient set (genetics) each point will map to a point in the phenotype set, and in the supervenient set (phenotypes) each adaptive strategy can map too many different points in the genotype set.

Teleological

Describes a doctrine that final causes exist, and thus that purpose is a part of nature. In the current context, teleology dictates that cancers exist for a (self-serving) purpose. Thus, we ask why, and not how, cancers behave the way they do.

Theory

A coherent group of general propositions that can be used as principles of explanation and prediction for a class of phenomena. A proposed explanation the status of which is still conjectural and subject to experimentation.

## Rights and permissions

Reprints and Permissions

Gillies, R., Verduzco, D. & Gatenby, R. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 12, 487–493 (2012). https://doi.org/10.1038/nrc3298

• Published:

• Issue Date:

• DOI: https://doi.org/10.1038/nrc3298

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