The evolutionary theory of cancer: challenges and potential solutions

Abstract

The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.

Figure 1|. Cancer evolution by natural selection can operate at multiple levels of biological organization at once.

a) There may be natural selection on groups of cells, here shown as stem cells and their non-stem cell progeny. In this example, the blue non-stem cells have a property (marked by a ´+´) that protects their stem cells from destruction by lymphocytes, and allows the colonies of blue cells to replicate. Yellow progeny lack (-) these properties, leading to the destruction of the yellow population by the lymphocytes. b) Below the level of the cell, extrachromosomal DNA (ecDNA) may increase the copy number of cancer-related genes (for example MYC) independent of the chromosomes. Similarly, transposable elements (TE1 and TE2) in the genome may replicate within the genome.

Figure 2|. Defining clones is a matter of dividing up the cancer cells tree.

a, The tree of cancer cells, with genetic, epigenetic, and phenotypic information overlaid. b, The cancer cells tree with clones identified through driver mutations. 3 clones are identified (white with whatever mutations the transformed cell had, blue with the occurrence of the blue mutation b, turquoise with the turquoise mutation t). c, The cancer cells tree with clones identified through epigenetic alterations. 3 clones are identified (white with the epigenetic state of the first transformed cell, red with epigenetic mutation r, yellow with epigenetic mutation y). They are not the same clones as in the genetic clones. d, Phenotypic clones. There are 2 cell types. The turquoise genetic clone is mixed and contains both cell types, while the white and blue genetic clones contain a different cell type. The yellow epigenetic clone is mixed, while the red and white epigenetic clones contain the same cell type. Are there 3 clones, 5 clones, or more?

Figure 3|. Clonal evolution is more complex than a bifurcating tree of cells.

Clones can use horizontal gene transfer (dotted arrows) to transfer heritable information, thereby breaking the assumption of vertical inheritance. The purple bean-shaped cells represent intracellular microorganisms, which evolve and have their own lineages indicated by the purple dotted lines. Elements of the cells can also be transmitted horizontally from cells, including non-malignant cells, to cancer cells, through absorption of extracellular vesicles, tunneling nanotubes, trogocytosis or cell cannibalism, which is represented by the transfer of cell surface receptors from the blue cell (for example a lymphocyte) to the gray cancer cell.

Figure 4|. Types of inheritance over various timescales.

Genetic inheritance may contribute at any time scale and persist throughout life. Niche construction by cancer cells may have selective effects lasting for days to months, though the exact timescale is unknown. Some entities such as cytoplasmic and cell surface proteins may be inherited for a very short period of time, likely just days. They may be important contributors to evolution by natural selection in case of abrupt and short changes in selective pressures such as cancer therapies.

Figure 5|. Explanatory power of clonal evolution.

When aiming to explain cancer in its entirety, evolutionary processes can explain only some, but not all cancer phenomena. Other theories, such as the cancer stem cell theory or some versions of the persister cell models provide complementary explanations for various phenomena in cancer. The clonal evolution model only captures parts of the causal role of evolutionary processes in cancer. There are thus opportunities to increase our current ability to provide evolutionary accounts of cancer, by integrating heredity, plasticity, reticulate evolution and clone diversity into the clonal evolution model. The proportion of cancer phenomena that can be explained by evolution is unknown.