CANCER AND EVOLUTION: A STORY OF CHEATERS AND REBELS Free

Review of: The Cheating Cell and Rebel Cell

Aktipis, A. 2020. The Cheating Cell: How Evolution Helps Us Understand and Treat Cancer. Princeton Univ. Press, Princeton, NJ, 256 pp. ISBN 9780691163840.

Arney, K. 2020. Rebel Cell: Cancer, Evolution, and the New Science of Life's Oldest Betrayal. Kat Ben Bella Books, Dallas, TX, 397 pp. ISBN 9781950665303.

In addition to being a major cause of mortality in humans, cancer is ubiquitous across the multicellular tree of life and thus has distant evolutionary roots. Despite this, oncologists and cancer researchers have only recently begun to integrate eco-evolutionary principles into their understanding of the mechanisms that underlie cancer and its treatment. The Cheating Cell by Athena Aktipis and Rebel Cell by Kat Arney are both timely books that challenge readers to rethink their traditional understanding of cancer and how we treat it. Both books strongly communicate the same major theme: Cancer emerges within multicellular organisms as a result of the same evolutionary processes that have shaped the evolution of individual organisms across the grand tree of life. Mutations in somatic cells may lead to the evolution of cheating cells that rebel against the rest of the organism. Natural selection may then favor these cells that selfishly proliferate uncontrollably to form tumors and metastasize in the body.

Although the content discussed in each book heavily overlaps, the authors each bring a unique perspective to the table. Aktipis’ The Cheating Cell reads like a deep and personal hypothesis coming from a researcher who has spent over a decade studying the evolutionary foundations of cancer. On the other hand, Arney's Rebel Cell takes a broad investigative approach by leading the reader through the major historical innovations and perspective shifts in cancer research through interviews with researchers from a variety of fields, including anthropology, genetics, and oncology. Both authors make clear the need for the scientific community to integrate this relatively novel eco-evolutionary framework into their perspective of cancer to improve our unified approaches to understanding and treating cancer. Ultimately, both books are engaging reads that have important implications for cancer researchers and practitioners alike and make a convincing case as to why this perspective shift is necessary for the overall field of cancer research moving forward.

Athena Aktipis begins The Cheating Cell by outlining the thesis of her book along with a description of what led and inspired her to pursue cancer research from a largely theoretical perspective. Aktipis began her academic career as an evolutionary psychologist studying cooperation and conflict in humans. Specifically, she was interested in a classic evolutionary paradox: How can natural selection account for the existence of cooperation in large social groups in the face of cheaters? It was not until she began her work as a postdoctoral researcher with John Pepper, a pioneer in the study of cancer evolution, that she realized the same rules that govern the evolution of cooperation and conflict in organismal-level social groups can also be applied to the cellular societies that make up multicellular organisms. Aktipis’ thesis is that cancer occurs when the emergence of “cheating cells” leads to a breakdown in multicellular cooperation, hence the title of her book.

In contrast, Kat Arney begins the Rebel Cell by emphasizing the disappointing direction in which the “War on Cancer” perspective has taken cancer researchers and practitioners. She argues that many modern treatments that aim to eliminate cancer can actually make the cancer come back stronger, as the elimination of cells sensitive to treatments such as chemotherapy leaves the resistant cells to flourish. Further, there may be financial incentives for insurance companies, pharmaceutical companies, and medical providers associated with these reactive treatments thereby facilitating their continued use. To advance the effectiveness of cancer therapy, it is essential that researchers shift toward an eco-evolutionary perspective of cellular societies, which will allow for the development of strategic treatments that attempt to manage cancer, rather than destroy it.

The central tenet of both books is that cancer is an inevitable consequence of multicellular living. In Chapter 3 of The Cheating Cell and Chapter 2 of Rebel Cell, Aktipis and Arney describe why life on Earth made the jump to multicellularity. Ultimately, the efficiency generated from the ability to divide labor into specialized tasks such as movement, digestion, and reproduction, and so forth allowed multicellular organisms to outcompete single-celled organisms (Aktipis et al. 2015). However, multicellular living set the stage for a new problem: the risk of developing cancer (Trigos et al. 2018). Early multicellular organisms therefore faced a strong selective pressure to regulate multicellular cooperation and resist the proliferation of any cheaters. In other words, the cellular mechanisms that keep cancer in check are as old as multicellular organisms themselves. These mechanisms include cell cycle checkpoints to restrict proliferation, and controlled cell death (apoptosis) when a potential cheater arises via mutation.

In Chapter 4 of The Cheating Cell, Aktipis describes the progression of cancer from the perspective of individual development in multicellular organisms. As individuals age, each cell division that occurs for processes such as growth and tissue repair allow the potential for mutation in somatic cells. Given that growth and tissue repair are essential for the development and maintenance of individuals, Aktipis explains how organism must carefully balance how much cell proliferation is controlled and regulated to minimize the risk of cancer without compromising these processes. In other words, if there is too much cancer resistance, then the organism may face other fitness costs related to growth and/or healing. This phenomenon can explain why cancer persists in multicellular organisms despite the resistance mechanisms described above. Aktipis explains how this can lead to many observable phenotypic trade-offs within populations, where individuals that express a phenotype associated with higher fitness often have an associated increased risk for developing cancer. For example, women with mutations on the BRCA1/2 tumor-suppressing genes have an increased lifetime risk of developing breast cancer. However, some studies show that woman who are carriers of BRCA1/2 tend to have more offspring, and that these mutations can persist within multigenerational lineages, suggesting a potentially fertility advantage associated with the mutations (Smith et al. 2012). There is also evidence to suggest a positive association between height and cancer risk in humans, a risk that may be maintained over time due to increased competitive success in males (Nunney 2018). Although these are intriguing areas of research, both associations have been met with contradictory results that suggest they may not be generalizable across populations. Future research should continue to investigate how trade-offs may maintain alleles associated with increased cancer risk in humans.

In Chapter 3 of Rebel Cell, Arney explores the innovations that have helped advance our understanding of the proximate causes of cancer. The discovery of chromosomal abnormalities in cancerous cells in the early 20th century led to the idea that cancer was the result of some sort of problem with the genetic material of the cell (even though the structure of DNA itself was not yet well understood). This concept, eventually coined the “somatic mutation theory of cancer,” sparked an effort to uncover what environmental factors can lead to these “cancerous” mutations by exploring the associations between cancer risk and factors such as smoking, exposure to UV, and certain diets (i.e., potential carcinogens). Both authors point out the important concept that the modern environments inhabited by humans are vastly different from those inhabited for most of our evolutionary history. Thus, we may not be adapted to optimally resist cancer in our current environment. This environmental mismatch may explain why humans have a relatively high risk of cancer, considering that much of our exposure to many novel carcinogens, such as smoking cigarettes, are relatively recent innovations. In Chapter 4, Arney explains how the leap in genetic techniques in the mid-late 20th century progressed the modern gene-focused view of cancer. Once researchers were able to identify that most cancer cells had mutations on genes that were associated with the promotion of cell division (later coined as “oncogenes”) or with the suppression of tumors, their goal became to find all the genes associated with these processes with the logic that they could be potential indicators of cancer risk and hence treatment aimed at targeting these genes. However, as time went on, identifying mutations associated with cancer proved difficult as it became apparent that both healthy and cancerous cells were littered with mutations in their genomes. Integrating the eco-evolutionary framework regarding the mutation and subsequent natural selection of selfish cells allowed researchers to understand why some cells with a patchwork of mutations remain part of totally healthy tissue, and why others turn into deadly tumors.

Given that cancer originated in some of the first multicellular organisms, both authors continue to discuss the ubiquity of cancer across the multicellular tree of life, and factors that may explain variation in cancer risk across species. Cancer has been observed in nearly all vertebrates and is also widely documented across invertebrates, plants, and fungi (Aktipis et al. 2015). Comparative oncology involves comparing the ecological and phylogenetic characteristics of species with similar cancer risks to help identify commonalities in mechanisms related to cancer protection (Boddy et al. 2020). When it comes to variation across species, both authors explain nicely why some species are at higher risks of developing malignant tumors within their lifetimes (Chapter 5 in The Cheating Cell and Chapter 1 in Rebel Cell). Theoretically, if every cell division provides an opportunity for cancer to emerge, then large and long-lived organisms should have an increased cancer risk compared to small and short-lived organisms, but there is no such observed relationship between cancer risk and average body size across animal species (Caulin and Maley 2011). This incongruency is known as “Peto's Paradox,” after Richard Peto, who first observed the trend (Peto et al. 1975). However, there does appear to be a positive relationship between lifespan and cancer resistance across species (Boddy et al. 2020). For example, elephants have a lower recorded risk of cancer compared to many smaller species, including humans. Further investigation has revealed that elephants have evolved multiple copies of TP53, a gene that suppresses tumors via promoting apoptosis in response to DNA damage (Tollis et al. 2021). Other long-lived species such as bats and naked mole rats also appear to be remarkably resistant to cancer. From an evolutionary perspective, it appears that because these animals are long-lived and reproduce to a relatively old age, natural selection has resulted in cancer resistance mechanisms that maximize reproductive success across their life spans. This comparative approach is an important way forward for uncovering the diverse cellular mechanisms associated with cancer resistance across the tree of life and for informing us as to why some animals appear to get cancer a lot, and some do not.

Evolution is a population-level process that responds to changes in ecological systems, and the progression of cancer lineages is governed by these processes. In Chapters 6 of The Cheating Cell and Rebel Cell, the authors explore this concept by discussing how cellular cheating occurs within the ecological context of the multicellular body. Aktipis explains how aspects such as access to resources, attack from the immune system, and even both competition and cooperation can all act as selective pressures that shape the trajectory of the progression of a relatively harmless lineage of cells with some mutations into an aggressive tumor (Aktipis and Nesse 2013). For example, when immune cells detect abnormal cells, they produce factors that stop proliferation and induce apoptosis. In a similar manner to prey evolving strategies to resist predators, cancer cells have evolved mechanisms that allow them to evade immune responses, such as the loss of molecular markers on the cell surface that the immune system uses to identify them as a threat (Gabrilovich and Pisarev 2003). Furthermore, as the evolution of cancerous lineages progresses, the novel phenotypes expressed by cancer cells may change the microenvironments they inhabit. This generates novel selective pressures and leads to a feedback loop between the ecology of the tumor and its evolution, similar to what we observe in organismal communities (Johnson and Stinchcombe 2007). For example, early-stage cancer cells selfishly exploit available resources in the microenvironment for growth. As these resources become depleted, selection favors cells that are able to help bring in new resources through the tumor, such as signaling for the growth of new blood vessels. The depletion of local resources may also create conditions that favor cells that can disperse and colonize around the body via metastasis, thus vastly increasing the harmfulness of the cancer to the body. This ecological understanding is essential for progression of cancer treatment, as the manipulation of microenvironments is one potential avenue for controlling and managing the evolution of tumors.

Both books conclude with chapters outlining how an eco-evolutionary-informed view can provide opportunities to improve how practitioners treat and manage cancer in humans. In Chapter 7 of The Cheating Cell and Chapters 9 and 10 of Rebel Cell, the authors explain how the mainstream treatment approach to engage in an “all out war” to exterminate cancer falls short in light of the eco-evolutionary framework discussed throughout their books. Similar to how the overuse of chemical pesticides can lead the evolution of populations of pesticide-resistant pests, the overuse of chemical treatments aimed to destroy cancer cells (and also have deleterious effects on healthy cells) can cause cancers to become more aggressive by leading to the evolution of lineages of cells resistant to therapy. One of the first practitioners to recognize and address this issue was Bob Gatenby, who pioneered the approach of adaptive therapy. Adaptive therapy involves providing patients with chemotherapy doses that shrink tumors, but that are dosed low enough to keep some sensitive cells alive. This way, even though the tumor is bound to regrow, the treatment can be repeated to keep tumors at a manageable size (Gatenby et al. 2009). So, rather than trying to outright destroy the tumor and leaving the body with a variety of unwanted side-effects, controlling it in such a manner appears to offer substantial benefits to the quality of life, especially if detected early. The authors also emphasize the importance of specialized and strategic treatment for different individuals. An important aspect of the eco-evolutionary framework is that no two cancers are the same. Aktipis describes the Evo-Eco Index used to quantify the nature of a tumor, which includes two dimensions: the amount of clonal diversity currently present, and the rate in which mutations are accumulating in the tumor over time. By understanding the specific eco-evolutionary features of the tumor, treatment can be tailored to manage the cancer as something that individuals can live with. Arney concludes Rebel Cell in Chapter 11 with a powerful and personal summary of her overall message: The fact that cancer is a natural consequence of multicellular life contradicts idea that cancer can be “cured” from the human population through outright “elimination.” This realistic perspective of cancer needs to become the norm, so we can move closer toward a future that maximizes the quality of life of those with cancer, and those indirectly affected by it.

The Cheating Cell and Rebel Cell are essential reads for anyone in a profession related to cancer, and highly recommended for any reader interested in expanding their understanding of how evolutionary theory can be applied to human health. For all purposes, both books offer substantial and compelling insight into a common topic and reading either of the two books is likely to be inspirational for evolutionary biologists by getting them to think about how general evolutionary theory can be applied to novel systems outside of their current specializations. Readers with a background in cancer biology looking to learn more about this novel eco-evolutionary perspective on cancer may find Aktipis’ The Cheating Cell to be a more efficient read. However, a reader looking to learn about cancer from a broader perspective is likely to gain more from Arney's Rebel Cell. Both Aktipis and Arney acknowledge the importance of getting these ideas out to the world, and both authors coincidentally express this by co-opting Dobzhansky's famous phrase by stating, “Nothing in cancer biology makes sense except in the light of evolution.” Ultimately, the addition of the word “cancer” to Dobzhansky's quote appears a bit redundant, as the integration of eco-evolutionary perspectives is something that scientists from all areas of the life sciences, including medical researchers and practitioners, can certainly benefit from as science continues to become an increasingly interdisciplinary endeavor.

AUTHOR CONTRIBUTION

DCSF wrote the manuscript.

ACKNOWLEDGMENTS

I thank J. Smith, M. Heidemann, and P. White for their mentorship, insightful discussions, and helpful comments on the manuscript. I also thank the National Science Foundation for their funding of the EvoMedEd project, and N. Johnson and T. Chapman for additional comments on the manuscript.

LITERATURE CITED