Cancer evolves. That much is known and agreed upon. Researchers still, however, debate the detailed picture of how cancer came to be and why it still plages our species is subject to debate. Studying cancer through an evolutionary lens could provide answers to these questions. Why we get cancer, how it develops within the individual. It might also offer us a way to treat the disease.

Studying cancer through an evolutionary lens could provide answers to the questions of why we get cancer and how it develops within the individual.

Many date the origin of cancer as far back as the beginning of multicellularity. A collection of cells working together to create a functional organism is not tiny feet. It is one of the several bottlenecks life had to go through to evolve into what it is today. Each cell's natural and ordinary state is to maximize growth and reproduction, even at the expense of others. Cooperation only becomes possible when these cells find a way to limit their potential growth for the benefit of the whole organism. The unfettered growth we call cancer today may be the breakdown of this collaboration. Having rouge cells growing uncontrollably and cannibalizing the body is as old as multicellular organisms. And perhaps, this disease is here to stay.

The other sense in which cancer evolves is in the individual instances of the disease. Mutations that drive the development and progression of cancer turned out to be far more common. They occur so frequently that it is hard to imagine any of us free of cancer on any given day. However, most of the upstart cells do not make it. But it only takes a single successful cell to create a tumor. Once the seed is sowed, variations among its progeny initiate an evolutionary process. With the pressures imposed on the cancer cells, selection takes over. Eventually, a cell variant dominates the tumor mass. There are other parallels between the evolution of tumors and that of the species; evading the body's immune system, migrating to distant organs, and resisting interventions.

The problem with conventional therapy

The primary issue with conventional cancer therapies is not that they do not work. In many cases, they do. However, relapse is a living possibility for most cancer survivors. Viewing relapse and resistance in the light of evolution sketches a grim picture. Therapy with the goal of elimination disproportionately kills sensitive cells. While this could terminate a substantial fraction of the tumor mass, it creates a space for cells to fill. Regrowth is almost inevitable.

The primary issue with conventional cancer therapies is that relapse is a living possibility for most cancer survivors.

Scientists have unfailingly recognized this parallel with population dynamics. Many also believe that using these evolutionary forces against cancer is possible. Several ideas have made headway. Some are at different stages of development, from the entirely theoretical to the being tried in animal models and even humans. All rely on exploiting the evolutionary and ecological principles that govern cancer development. Three of these are worth mentioning in some detail.

Adaptive therapy

Adaptive therapy recognizes the evolutionary dynamics within the tumor in response to treatments. Cancer drugs first extinguish the susceptible cells; most do not come around to destroy the entire tumor. Therefore resistant cells would have the opportunity to grow to occupy the vacancy. By using small doses of the drugs, symptoms improve. The treatment is then withdrawn, allowing sensitive cells to proliferate again up to a predefined standard. Then the cycle is repeated. This form of therapy departs from conventional ones. Adaptive regimes do not aim to eliminate but manage the disease to enhance patient survival and quality of life.

Adaptive regimes do not aim to eliminate but manage the disease to enhance patient survival and quality of life.

The cost of being resistant

For a cancer cell to respond and adapt to drugs, it must dedicate resources that could otherwise be spent on division and proliferation. The cost of resisting can therefore be leveraged in a treatment approach. A drug can induce specific adaptations in cancer cells. The mere expenditure of adapting can hinder growth or make the cell vulnerable to another drug. Medications can be combined or used sequentially to capitalize on these costly adaptations.

Preventing adaptations

With the understanding of how cancer cells adapt to therapy, mixtures of drugs can be used to block it. One drug can aim to eradicate the tumor, and another to prevent the cells from evolving adaptations. This strategy simultaneously takes advantage of the established understanding of cancer evolution with Darwinian mechanisms and beyond. Namely, several non-Darwinian mechanisms have been recognized to contribute to developing resistance and are not being used for therapy.

References

• Vendramin, R., Litchfield, K., & Swanton, C. (2021). Cancer evolution: Darwin and beyond. The EMBO Journal, 40(18). https://doi.org/10.15252/embj.2021108389
• Gatenby RA, Brown JS. The Evolution and Ecology of Resistance in Cancer Therapy. Cold Spring Harb Perspect Med. 2020 Nov 2;10(11):a040972. doi: 10.1101/cshperspect.a040972.
• Ujvari, B., Roche, B., & Thomas, F. (2017). Ecology and Evolution of Cancer. In Ecology and Evolution of Cancer.