By Afton Widdershins

If you took a biology class during your school years, you may be familiar with the concept of evolution, the idea that living things acquire changes that they can pass on to their offspring. These changes begin as tiny, random mutations acquired as genetic information is copied imperfectly from parent to offspring. Over long stretches of time, these small changes pile up into large differences that can even result in the development of new species. The field that studies this process is known as evolutionary biology, and it attempts to understand questions such as how humans evolved from our species’ ancestors.

Even now, evolution has huge impacts on our health and well-being, and this idea is explored by a field known as evolutionary medicine. This discipline seeks to understand both diseases and how our bodies respond to them. Examining medicine within the context of evolution helps us understand why we get certain diseases and provide new ideas for how to treat them. As an example, let’s explore what evolutionary medicine teaches us about cancer!

Why do humans get cancer? Trees don’t get cancer the same way humans do, so why haven’t we evolved to get rid of cancer? One reason is that natural selection is limited on what it can influence.

Natural selection (Fig. 1) is an evolutionary principle that affects traits that

1. Have variation
2. Influence the ability of an organism to survive and/or reproduce
3. Can be inherited by an organism’s offspring

This means that natural selection will most directly influence traits that impact a human’s ability to have healthy kids and will have less ability to influence what happens to our bodies at an old age. Many cancers develop when people are older, and thus natural selection is unable to reduce our risk of getting cancer.¹

Another evolutionary principle that informs why humans get cancer is the concept of trade-offs (Fig. 2). A trade-off, in the context of evolution, is when natural selection for a trait that is beneficial can result in the simultaneous selection for a negative trait or against a positive one.

For example, humans, during our evolutionary history, developed a highly invasive placenta. The placenta is an organ that forms during pregnancy to help nourish the growing fetus by delivering oxygen and nutrients. To access nutrients, fetal stem cells must invade, or grow into, the blood supply in the parent’s uterus. A more invasive placenta means a fetus can get more nutrients from its parent, which leads to a growth advantage early in life. The ability to move through and invade other tissues is normally turned off in many of our adult cells, which require controlled interactions with neighboring cells to build healthy tissue. However, mutations acquired by cancer cells can turn this latent, or turned off, ability back on, priming the cancer to spread to multiple parts of the body, a process known as metastasizing. As such, the increase in placental invasiveness is associated with a higher risk of metastasis, and the trait is a trade-off. It benefits us early in our life to access more nutrients from our parents, but the trait also puts us at risk for more serious cancer later in life.¹

Now that we’ve explored some evolutionary reasons why cancer is a disease that humans can get, let’s look at how doctors and scientists can use evolutionary theory to better treat cancer.

Cancer is a disease of uncontrolled cell growth. As part of this runaway cell growth, a cancer starts to evolve selfishly, forgoing what is good for the body as a whole in favor of what benefits the tumor. Oncologists, or cancer doctors, impact this process when they prescribe treatments like chemotherapy because they change which cells will be most successful. The cells that are resistant to chemotherapy are more likely to survive, creating an environment where the medical treatment selects for cells with greater resistance.² Over time, this can result in all of a person’s cancer cells becoming immune to treatment, creating a cancer that’s much harder to care for.³

Considering cancer in the context of evolution has resulted in new ideas for how to treat the disease. One idea is adaptive therapy (Fig. 3), which tries to manage cancer by controlling the number of resistant cells, rather than by trying to kill as many cancer cells as possible. Most adaptive therapy strategies attempt this by maintaining a population of normal, non-resistant cancer cells. These cells compete with the other resistant cancer cells for space and for nutrients, which limits the ability of the resistant cells to take over.³

To maintain this population of non-resistant cells, the focus of adaptive treatment is to partially reduce tumor size rather than to attempt complete elimination, and so patients are often only given their chemotherapy treatment for just long enough to achieve a particular population reduction goal. Then patients stop receiving chemotherapy for a period known as a “drug holiday” until their tumor requires reduction again.⁴ This strategy may seem odd in that it decreases the total number of cells killed, but it also means that a population of non-resistant cells are maintained. From an evolutionary perspective, this increases the competition that the resistant cells while also decreasing their advantage, preventing the resistant cells from becoming the entire tumor population.²

While this strategy doesn’t usually cure patients of their cancer, it can extend the amount of time a treatment works for some patients while also appropriately managing their disease. This strategy has seen success in clinical trials for patients with metastatic, or wide-spread, prostate cancer, drastically increasing the time until a patient’s cancer worsens and reducing the amount of drug they have to take.⁴ 

Adaptive therapy is not the only cancer treatment idea that evolutionary principles have inspired. More curative approaches utilizing evolutionary double-binds, where the development of resistance to a current therapy creates a susceptibility to a different treatment, and extinction vortexes, where the events that lead to the extinction of species inspire new ways to design treatment schedules, are currently being studied in the lab and in clinical trials.³ Cancer is only one of many diseases to which evolutionary medicine brings novel insights. The study and practice of medicine can only be strengthened by exploring it from new perspectives!

TL:DR

• Evolutionary medicine studies how evolution impacts human health and disease.

• Our evolutionary history puts us at a higher risk for cancer than other species.

• The way cancer evolves gives us new ideas for how to treat cancer.

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References

1.         Stearns, S. C. & Medzhitov, R. Evolutionary medicine. (Sinauer Associates, Inc., Publishers, 2016).

2.         Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive Therapy. Cancer Research 69, 4894–4903 (2009).

3.         Gatenby, R. A. & Brown, J. S. Integrating evolutionary dynamics into cancer therapy. Nat Rev Clin Oncol 17, 675–686 (2020).

4.         Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat Commun 8, 1816 (2017).

5. NIH(2020). How Adaptive Cancer Therapy Works. Retrieved from https://visualsonline.cancer.gov/details.cfm?imageid=12592#:~:text=In%20adaptive%20therapy%2C%20drugs%20are,of%20the%20drug%2Dresistant%20cells.