9 Cancer as a evolutionary disease
Cancer has long been understood as a disease triggered by DNA changes, however, these are only the starting point for a more complex process driven by the same principles that we today know drive the evolution of species.
These were first detailed by Darwin (On the origin of species, 1859) and describe how species are shaped over generations by natural selection resulting in a gradual change of heritable characteristics or traits (Figure 9.1).
Darwin realised that genetic variation in populations exists and that individuals and species that share a common environment (biotope) compete for resources and differ in their level of adaptation to the environment. Individuals with advantageous traits will on average have a survival or reproductive advantage while those with negative traits will be at a disadvantage. Because these traits are based on the genetic variation between the individuals they can be passed on to the offspring. The process of natural selection against those traits will be repeated many times. Therefore, over time, there will be more of those individuals that have these advantages and less of those who are at a disadvantage. This means that those individuals with traits which are advantageous will become more prevalent in a population while those which are disadvantageous will disappear.
The ideas that the principles of evolution might also apply to cancer cells was first proposed by (Nowell (1976)). When we consider these ideas in the context of cancer cells there are clear parallels (9.1):
- Random mutations or epimutations can lead to changes in the expressed proteins which, in turn, can lead to a changes of phenotype (i.e. observable characteristics).
- Such changes are heritable, i.e. they are passed on to subsequent generations of daughter cells or clones.21
- As different cells will experience different heritable changes this leads over time to phenotypic variation within a population.
However, if mutations are random why do all cancers independent of risk factor, exposure or tissue type develop in the typical sequence i.e. showing hyper-proliferation, invasion, and metastasis?
- Phenotypical differences between cells in a shared environment also allow selection
- Cells in which the random mutations have led to traits which bring and advantage will have a survival advantage and/or a reproductive advantage by dividing more often.
- As a consequence of this natural selection process the clones with successful cellular phenotypes will expands
- Cancer development is a multi-step process because the cancer cells will potentially experience further mutations. Each of these repeated mutations increases overall variability and allows for potential selection.
- Thus over time the population of cancer cells in a tumour undergoes repeated rounds of selection with disadvantageous traits eventually disappearing and advantageous traits accumulating in those clones.
Thus in cancer the evolutionary process is driven by step-wise somatic cell mutation and clonal selection. The cancer cells we typically find in a tumour at diagnosis have already undergone multiple rounds of selection and will have accumulated traits that allow the transition from the locally proliferating tumour to those which show signs of invasion and eventually metastasis.
9.1 Somatic Evolution
Somatic cells in the body are constantly exposed to insults that can lead to DNA mutations, chromosomal changes, or epigenetic modifications. These changes can be passed on to daughter cells after mitosis. The changes can lead to downstream changes in protein expression which can either lead to a gain or loss of function or can be silent with respect to the cell’s phenotype.
Over time heritable change can accumulate in various cells in a tissue thus leading to variability. Damage to specific genes involved in DNA repair or maintenance of chromosomal integrity could potentially lead to further acceleration of this process. Thus heterogeneous cell populations emerge. Within their environment these cell populations are exposed to selective pressure.
Consequently cell populations evolve in response to the selective pressure. Cells with mutations that have resulted in a favourable phenotype will have advantages and will grow relatively more leading to clonal expansion.
As these clones are exposed to further mutations/heritable changes they start to acquire more and more characteristics that give a evolutionary advantage. As a consequence these cell populations become more and more varied and with additional mutations leading to additional traits that can be selected for the cancer cell populations gradually take on the characteristics of the malignant tumour based on on-going somatic evolution. The longer this process of somatic evolution continues the higher the level of variability/heterogeneity is likely to be and the higher the likelihood will be that clones evolve that could be resistant to specific drugs.
9.2 Clinical Consequences of Somatic Evolution
Interestingly, there is now increasing clinical evidence supporting the notion of cancer as an evolutionary driven disease. Clinical studies looking at the development of individual cancers have been able to reconstruct a ‘phylogenetic’ tree mapping the specific mutations that lead to a branched evolution of the different clones. This has for example been mapped in detail for patients with metastatic renal cell carcinoma (Gerlinger, Rowan, and Horswell (2012)) and is illustrated for an individual patient in figure @ref(fig: 6-somatic-evolution-kidney-cancer).
It is evident that cancer cell population with in the primary tumour have become heterogeneous as heritable changes create different clones, and the different populations coexist and compete. Importantly, this process never stops, i.e. even when cancer cells have metastasised this process continues in those metastatic sites. These diverse populations then evolve, i.e. depending on the selective pressure and the advantageous, neutral, or disadvantageous nature of the underlying mutations some will have reproductive or survival advantages leading to the selection of clones with advantageous mutations and over time to the accumulation of such mutations and thus the evolution of more malignant clones.
Early diagnosis and treatment is important because the longer the process of somatic evolution continues the higher the chance that the tumour will contain a diverse group of malignant cancer cell clones.
It is important to appreciate that ‘fitness’ always needs to be understood in the context of the cells’ environment or histological biotope. So other cancer cell clones, non-cancerous immune cells, fibroblasts, endothelial cells and even extracellular matrix shape this environment. Furthermore, when tumour cells are exposed to chemotherapy or other anticancer drugs this therapy now also applies selective pressure. Ideally, the therapy kills alls cancer cells and the patient is ‘cured’; however, when we have heterogenous populations there is also a risk that there may be clones that are somewhat more resistant to the therapy. With most of the competing cells destroyed there is now a risk that the resistant clone now has a significant survival advantage and will start to proliferate strongly. This may clinically lead to a re-occurence of the tumour which when treated now with the same agents would have become resistant.
Somatic evolution and ‘fitness’
Having illustrated the important role of somatic evolution for cancer progression the next section will consider the question
- What properties give cancer cells a survival advantage?
- What mutations can lead to specific advantages?
- Do all cancer cells have these?
[Each time a cell divides this ‘parent’ cell creates genetically identical daughter cells. A clone is a line of cells derived from the same ‘parent’ cell that have identical genetic information. Each time a mutation hits a cell it DNA is changed from its ‘parent’ and ‘sister’ cells – and therefore it is a new clone. It will carry the history of mutations from all the previous (‘parent’) clones that it was derived from - these connected clones form a clonal lineage. In parallel, the ‘sister’ or ‘parent’ cells can of course also independently have further mutations which would start a separate clone. So each new mutation creates a new clone AND multiple mutations need to accumulate in one clone: If the original cell lines are clone 0 after introduction of a mutation we would have clone 1 and clone 0. Clone 1 is the same as the old clone 0 - apart from that new mutation. The next mutation now has to happen to the clone 1 and thus creates clone 2 (which has the genes of clone 0 + clone 1 + the new mutation). ]↩︎