Finally a review article on cancer evolution that I really enjoyed. Maybe because it’s not a Review but an Opinion piece: “Evolutionary dynamics of carcinogenesis and why targeted therapy does not work” by Gillies, Verduzco and Gatenby (GVG for short).
Extra brownie points for a provocative title.
The first publication on tumor heterogeneity
First of all, GVG extended my knowledge of the history of tumor heterogeneity by citing a paper from 1930:
Ö. Winge, Zytologische Untersuchungen über die Natur maligner Tumoren, Zeitschrift für Zellforschung und Mikroskopische Anatomie, 6. JUNI 1930, Volume 10, Issue 4, pp 683-735,
In 1930, Winge induced cancers in 80 mice with coal tar, and examined each tumour histologically. When possible, he counted chromosomes in multiple individual cells in the same tumour. In doing this, he documented that cells in the same tumour contained 35–138 chromosomes (normal diploid = 40). Although aneuploidy is a well-known hallmark of cancer, this study documented that a wide variation in chromosome number can occur in a single tumour.
Single cell analyses! Tumor heterogeneity! Sounds very modern.
A cancer is more than a genome
GVG describe principles a unifying theory of cancer evolution that places genomes in their tissue context:
[T]his potential ‘unifying theory’ places the evolution of the genome within a dynamically changing adaptive landscape, the outcome of which is genotypic and phenotypic heterogeneity, which both negatively affect the ability of targeted therapies to exert cancer control.
Their opinion is based on the following observation
[The success of evolutionary theory before molecular methods] reflects two often neglected first principles of natural selection: nature selects for phenotype, not genotype, and population changes are dependent on local environmental selection forces.
In cancers, evolution is fundamentally driven by environmental selection forces that interact with individual cellular strategies or phenotypes, which supervene cell genetics.
“Supervene” – such a fancy word. It means here that phenotypes matter more than genotypes, because (a) phenotypes are being selected for and (b) many genotypes can cause the same phenotype:
In multicellular organisms, many key traits are polygenetic so that the mapping of genetics to phenotypes is often imprecise. Thus, it is well recognized that common phenotypes in both cancer and normal cells can have myriad genetic causes.
Genomes are not enough
GVG sum up their view:
Understanding cancer as a disease starts with identifying crucial environmental forces and corresponding adaptive cellular strategies. Characterizing evolving populations solely by their genetic changes prior to understanding these fundamental evolutionary forces is likely to be futile.
Let me quote the last sentence again:
Characterizing evolving populations solely by their genetic changes prior to understanding these fundamental evolutionary forces is likely to be futile.
I completely agree with that.
Even though it means that the current state of the art is quite short-sighted. Analyzing tons of sequencing data is exactly what my group (and pretty much everyone else in the field) is currently focussing on, without any idea what the microenvironment in these tumors looked like …