7 -minute read

Fifty years ago, US President Richard Nixon declared a “war on cancer” when he signed the National Cancer Act. Despite fantastic progress on some fronts, overall it is clear that we are not winning this battle. Cancer remains one of the leading causes of human mortality. But what if the tired war-metaphor is getting it all wrong? Brimming with thought-provoking questions, The Cheating Cell looks at cancer through an evolutionary lens and forces the reader to radically reconsider cancer; not as a bug, but as a feature of life.

Athena Aktipis came to the research field of cancer evolution in the mid-2000s, just as it was getting a boost from various researchers, including Mel Greaves, who started to apply ideas from evolutionary biology to cancer research. She describes herself as working at the interface of cooperation theory, theoretical evolutionary biology, and cancer biology. Her background in psychology, with a specific interest in cooperation and conflict, might seem little relevant to cancer research but turns out to be highly appropriate.

The basic premise of this book is that cancer is an evolutionary phenomenon that has been with us for as long as life has been multicellular and is best thought of as cellular cheating. If that seems like a lot to take in, I am trying to distil into one sentence what Aktipis spends the first three chapters developing. Let us go through these in reverse order.

First, this notion of cheating. The hallmarks of cancer in humans is unchecked cell division, frequently forming tumours in the most unwelcome of places and, in some forms, spreading throughout the body in a process known as metastasis. But this is rather a narrow definition for understanding cancer’s deep evolutionary history. To compare organisms with a very different underlying biology, such as plants and animals, you need to think at a more fundamental level. What cancer cells are ultimately doing is cheating on the pact that cells form when cooperating to form a multicellular organism. They divide out of control, they refuse to self-destruct via programmed cell death (apoptosis), they hog the body’s resources, they do not stick to their assigned job, and they trash their environment, damaging and destroying the host’s body as they go.

“What cancer cells are ultimately doing is cheating on the pact that cells form when cooperating to form a multicellular organism.”

Second, this notion of its deep history. The option for some cells to go rogue and cheat became available as soon as life evolved multicellularity. As also further explored in chapter 5, some form of cancer is found in almost every animal group and even in plants, where it is known as fasciation. This chapter also explores Peto’s Paradox: how larger body size is associated with increased cancer risk within, but not between species. Large and long-lived species consisting of many cells, such as elephants and whales, are very resistant to cancer.

Third, this notion of an evolutionary phenomenon. Individual cancer cells reproduce rapidly and, just like organisms, are subject to natural selection. Populations of cancer cells show variation, heritability, and differential fitness—this is how they thwart our medical interventions, developing resistance to drugs and chemotherapy. Even if the time-scale is short and cancer ultimately kills its host, until then the calculus of evolution through natural selection still applies. Furthermore, selection is happening simultaneously at multiple levels. There is an arms race between rapidly evolving cancer cells and the body that, through division of labour, can draw on more complex defence strategies. Aktipis introduces you to three mechanisms that offer a certain redundancy in keeping cells from misbehaving. There is the intrinsic mechanism formed by the cancer suppressor gene TP53 that acts as a central node, incorporating information from many sources to decide whether to initiate DNA repair, apoptosis, or block cell replication. There is a neighbourhood mechanism, with cells requiring so-called survival signals from their neighbours so as not to initiate apoptosis. And there is the systemic mechanism of our body’s immune system detecting and destroying inappropriately behaving cells. Cancer can break or hijack all of these mechanisms.

Probably the biggest eye-opener for me was what I mentioned first: cancer being a feature, not a bug. In chapter 4, Aktipis outlines how cancer is with us from “womb to tomb”. The reason evolution has not overcome cancer is trade-offs. The very processes that, when they malfunction, cause cancer are the basic mechanisms that, when they function, allow us to exist as multicellular organisms in the first place. “Many important systems that help us survive and thrive require cells to do things that are “cancer-like” including proliferating rapidly, moving around the body, and invading tissues” (p. 55). Think of wound healing and tissue regeneration, for example. Aktipis introduces the metaphor of life walking a tightrope: there needs to be enough cellular freedom to allow an organism to grow and develop, but not so much that cell division runs rampant. This, here, is why the war metaphor is unhelpful: “We can’t completely eradicate something that is fundamentally a part of us” (p. 10).

“The very processes that, when they malfunction, cause cancer are the basic mechanisms that, when they function, allow us to exist as multicellular organisms in the first place. […] This, here, is why the war metaphor is unhelpful […]”

Aktipis has many more arrows to her bow. A long sixth chapter probes the frontiers of cancer research by asking what lesson from ecology we can apply to the tumour’s microenvironment. Can dispersal theory be applied to metastasis? Is the cooperation seen amongst cancer cells an adaptation, a by-product of other processes, or a transitory, random process? Can we draw lessons from kin selection theory or social insect colonies? What of the interaction between cancer and the microbiome? And can selfish genetic elements such as transposons influence our susceptibility to cancer? There is a huge blind spot here, claims Aktipis, in that current genomic sequencing technologies cannot detect extrachromosomal DNA, so it is hard to make links to cancer. The consequences could be dramatic: “the theoretical foundations of much of the field of cancer evolution would have to be reconsidered if cancer is, in part, a result of selection at the gene level favoring selfish genetic elements […]” (p. 158).

All of the above should force us to rethink how we treat cancer, leading to seemingly counterintuitive treatments. Our current strategies of radiation and chemotherapy rain down fire and brimstone but often lead to drug resistance. Rather than total eradication, adaptive therapies would aim for coexistence with tumours at a level that is not too damaging for the patient. For other cancers, feeding tumours and providing a comfy, stable environment could prevent the more disruptive result of metastasis. These are but some of the options and ideas considered here.

Aktipis is very interested in science communication and has enlisted Alex Cagan to provide infographics. I found her writing a tad repetitive in places, saying something in one paragraph and then repeating it in slightly different words in the next paragraph. Hopefully, the flipside of this particular quirk is that few people will be left feeling they did not understand concepts. And this is, in a way, a good thing: The Cheating Cell bristles with fascinating ideas, there are many other tangents and questions Aktipis raises that I have not mentioned.

“All of the above should force us to rethink how we treat cancer, leading to seemingly counterintuitive treatments.”

One final question to consider (I swear books are like buses sometimes; you wait for ages and then two come along in quick succession): how does this book compare to Rebel Cell? Published in 2020, science writer Kat Arney explores the same topic. Though I have not read it, a critical reviewer on Amazon UK felt it does not reference its sources properly. This is where The Cheating Cell shines, backing up statements with published research in a 30-page notes section.

The Cheating Cell makes for fascinating reading and forces a radical reconsideration of what cancer is and how we should deal with it. I will leave you with what I consider Aktipis’s most powerful and sobering call to action: “We have much to gain from accepting that cancer is a part of us and preparing for a long-term strategic interaction with it as an unpredictable and adaptive counterpart. It takes courage to face this truth and accept an uncertain future with cancer rather than hanging onto false hope that we will one day find a magical weapon that can target and eliminate cancer from the world.” (p. 182).

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Disclosure: The publisher provided a review copy of this book. The opinion expressed here is my own, however.

The Cheating Cell

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