# Beyond Peto's paradox: expanding the study of cancer resistance across species

Antoine Dujon, Amy M Boddy, Rodrigo Hamede, Rodrigo Hamede, Beata

Ujvari, Frédéric Thomas

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Antoine Dujon, Amy M Boddy, Rodrigo Hamede, Rodrigo Hamede, Beata Ujvari, et al. Beyond Peto's paradox: expanding the study of cancer resistance across species. Evolution - International Journal of Organic Evolution, 2025, 79 (1), pp.6-10. 10.1093/evolut/qpae158. hal-04938625

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# Beyond Peto's paradox: expanding the study of cancer resistance across species

Antoine M. Dujon<fnref n="1" />,<fnref n="2" />, ID, Amy M. Boddy<fnref n="3" />, Rodrigo Hamede<fnref n="4" />, Beata Ujvari<fnref n="1" />, ID, Frédéric Thomas<fnref n="2" />, ID

## Abstract

Peto's paradox, which highlights the lower-than-expected cancer rates in larger and/or longer-lived species, is a cornerstone of discussions at the intersection of ecology, evolution, and cancer research. It prompts investigations into how species with traits that theoretically increase cancer risk manage to exhibit cancer resistance, with the ultimate goal of uncovering novel therapies for humans. Building on these foundational insights, we propose expanding the research focus to species that, despite possessing traits beyond size and longevity that theoretically increase their cancer risk, exhibit unexpected cancer resistance. Testing Peto's paradox without interference from transient dynamics also requires considering species that are at an equilibrium between cancer risks and defenses, which is increasingly challenging due to anthropogenic activities. Additionally, we argue that transmissible cancers could significantly help in understanding how the metastatic process might be naturally suppressed. This research perspective is timely and aims to support the continued and in-depth identification of anti-cancer adaptations retained throughout evolution in the animal kingdom.

**Keywords:** comparative oncology, evolutionary mismatch, evolutionary medicine, wildlife oncology, tumor suppression, transmissible cancer

One of the most promising aspects of evolutionary medicine is the search for adaptations to diseases in species whose biological characteristics should make them vulnerable, yet this vulnerability is not observed (Natterson-Horowitz et al., 2023). For example, giraffes should be particularly prone to hypertension, but this is not the case (Zhang, 2012; Liu et al., 2021). Certain shrews, such as *Ptilocercus lowii*, primarily feed on fermented nectar and should therefore be susceptible to alcoholism, but again, this is not observed (Wiens et al., 2008). The explanation behind these paradoxes lies in evolution, which suggests that natural selection has favored during the course of evolution the development of specific adaptations against these diseases, thereby limiting their impact on fitness. Therefore, the study of certain species by biologists from this perspective can theoretically accelerate the discovery of novel treatments to combating human health challenges (Natterson-Horowitz et al., 2023).

A disease that has been particularly studied within this framework is cancer, with research centered around Peto's paradox. The focus has been on the idea that large-sized species and/or those with significant longevity should be particularly prone to cancer (Peto, 1977). That is because cancer is a problem of cellular mutations, and the more cells or the longer cells live, the higher likelihood of getting a cancer-causing mutation. However, if larger or longer-lived animals do not get more cancer, it is because adaptive mechanisms have

evolved to better prevent, combat, or tolerate malignant tumors (Roche et al., 2012; Caulin & Maley, 2011; Nunney et al., 2015; Vincze et al., 2022). Evidence indeed suggests that elephants and whales, for instance, have a lower cancer rate than predicted given their size and longevity. In recent years, deeper examinations have identified various specific anticancer defenses in large and/or long-lived animals, ranging from additional copies of tumor suppressor genes and enhanced immunity to improved DNA repair mechanisms and the presence of hyper-tumors etc. (see Nery et al., 2022; Trivedi et al., 2023 for reviews). Understanding these mechanisms not only provides insight into the biological strategies employed by these animals against oncogenic processes but also offers potential avenues for novel cancer treatments in humans (Somarelli et al., 2020). Indeed, by studying these natural anticancer defenses, scientists can develop innovative approaches to prevent, detect, and treat cancer, potentially translating these evolutionary solutions into medical advancements (e.g., Ferris et al., 2018; Thomas et al., 2018).

While Peto's paradox has primarily addressed the relationship between body size, longevity, and cancer risk (or correlated variables (Dang, 2015; Maciak & Michalak, 2015), we suggest that future research should also consider additional traits that may contribute to cancer resistance mechanisms, broadening the framework. While there have been notable and promising strides to study cancer risk beyond body mass

<footnote n="1">¹School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, Australia</footnote>

<footnote n="2">²CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290-Université de Montpellier, Montpellier, France</footnote>

<footnote n="3">³Department of Anthropology, University of California Santa Barbara, Santa Barbara, CA, United States</footnote>

<footnote n="4">⁴School of Natural Sciences, University of Tasmania, Hobart, Tasmania, Australia</footnote>

<footnote>Corresponding authors: School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, Australia. Email: a.dujon@deakin.edu.au (A.M.D.) and CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290-Université de Montpellier, Montpellier, France.
Email: frederic.thomas2@ird.fr (F.T.)</footnote>
and longevity, a vast amount of biodiversity is still underexplored. Any species with unexpectedly low cancer rates is of interest for discovering mechanisms of cancer suppression, as they may provide key insights into the biological strategies that have evolved to combat oncogenesis. For instance, species residing in naturally polluted environments for extended periods, exposed to mutagenic substances, inherently develop potent anticancer adaptations, regardless of their size or lifespan (Vittecoq et al., 2018). Research within mammalian species has revealed that those with highly invasive placentation surprisingly exhibit no greater susceptibility to malignant or metastatic cancers (Dujon et al., 2023; Boddy et al., 2020), contrary to theoretical expectations (Wagner et al., 2022). A probable explanation for these seemingly paradoxical findings mirrors that of Peto's paradox regarding size. Namely, the species most susceptible to cancer-related mortality due to a high cellular invasive potential are also the ones that have evolved the most robust anti-cancer defenses to mitigate this vulnerability. The relevance extends to domesticated animals as well, considering their historical exposure to conditions conducive to tumorigenesis. Remarkably, the domestication process has, at times, coincidentally favored the development of anticancer mechanisms (Thomas et al., 2020).

Sexual selection, a fundamental component of evolutionary biology, drives the development of traits that enhance reproductive success through mate attraction and competition. Although sexual selection might seem distant from Peto's original focus, these reproductive traits offer another layer to understanding how species manage cancer risk, further expanding the framework initiated by Peto's paradox. These traits, which often involve significant physiological and energetic investment, are theoretically predicted to increase cellular stress and proliferation, leading to higher mutation rates and inadvertently raising the risk of cancer within the animal kingdom (Andersson, 1994; Shuker & Kvarnemo, 2021; Tosto et al., 2023; Dujon et al., 2022; Rubin, 2015; Boddy et al., 2015). For instance, traits such as elaborate ornaments or exaggerated weaponry, often result from increased levels of hormones like testosterone or other growth factors (e.g., Summers & Crespi, 2010), which have been linked to tumor growth (Watts et al., 2021). Additionally, the competitive nature of mating rituals can lead to physical confrontations among rivals, potentially causing tissue damage and inflammation, both of which are associated with cancer development (Coussens & Werb, 2002). The production and maintenance of elaborate ornaments necessitate intense cellular proliferation, which in itself can increase the risk of cancer (Boddy et al., 2015). Moreover, the energetic demands of producing and maintaining sexually selected traits may divert resources away from immune function (Møller et al., 1999), weakening the body's ability to combat cancerous cells. Finally, the pursuit of mating opportunities may drive animals to take greater risks, exposing them to environmental carcinogens or pathogens (Dujon et al., 2020b).

Despite all these potential links between sexually selection traits and cancer phenotypes, there is currently no evidence of significant cancer incidence in species subject to intense sexual selection processes, even in zoo conditions. In fact, some cases have the opposite trend—where there is less cancer reported in species with evidence of sexual selection. Take, for example, the annual growth of antlers in deer, characterized by rapid cell proliferation, which shares molecular pathways with cancer development (Wang et al., 2019). Yet, unlike

cancer, this proliferation is tightly regulated and typically does not progress into malignant tumors (Li et al., 2023). Instead, the process demonstrates a remarkable example of controlled growth, akin to “cancer under control.” Insights gained from studying this natural phenomenon may offer valuable perspectives for cancer research, potentially revealing mechanisms for regulating cell growth and proliferation that could be harnessed for therapeutic purposes (Yang et al., 2017; Chonco et al., 2021; Tang et al., 2015).

While secondary sexual traits may increase cancer risk within a species, they could also indicate a selection for effective anticancer mechanisms among species strongly subjected to sexual selection. The evolution of secondary sexual characteristics, particularly the most extravagant ones, would therefore be constrained by the cancer risk associated with their bearers and conditioned by the existence of concomitant selection for adequate anticancer defenses. If this scenario is true, it predicts that the most extravagant secondary sexual characteristics are also of recent evolutionary age. To test this hypothesis, it would be necessary to determine the age of appearance of these traits in the evolutionary history of species and to verify if the evolution of this sexually selected trait is correlated with the emergence of anticancer defenses, or to other limiting factors.

Most work on Peto's paradox examines species whose cancer defenses are aligned with their cancer risk. However, some species may have adaptive lag, where their evolutionary defenses are temporarily mismatched with the cancer risk. For example, studies on urban wildlife exposed to environmental pollutants, such as city-dwelling birds or mammals exposed to high levels of mutagenic stress (Sepp et al., 2019), suggest that species may face a heightened risk of cancer due to rapid environmental changes. These organisms may experience short-term increases in cancer susceptibility until they evolve more robust defenses (see however Yagmur et al., 2020). For species in equilibrium, cancer risk is expected to be rare or even absent during the pre-reproductive and reproductive phases and mostly present only in the post-reproductive phase for those species who live past post-reproduction. Current wildlife species, at least those in their natural ecosystems, are exposed to an increased oncogenic risk due to anthropogenic activities (Giraudeau et al., 2018; Pesavento et al., 2018). This mismatch between cancer risk and defenses can bias the data because it theoretically leads to at least three types of evolutionary processes that are likely to occur sequentially (Dujon et al., 2024). First, it is predicted that individuals exposed to high mutagenic sources will upregulate their anticancer defenses, mitigating more or less efficiently the risks to varying degrees throughout all stages of their lifespan. This phenomenon is likely to alter the biology of species due to trade-offs and will also generate noise that obscures the link between observed cancer statistics and cancer defenses. Second, it is expected that individuals and/or species subjected to abnormally high cancer risks will adjust their life history traits (e.g., phenotypic plasticity and/or genetic selection), notably by maximizing their early reproductive effort (e.g., Boutry et al., 2022; Jones et al., 2008) and/or by shortening the length of the reproductive period to allocate more resources to grandparent care (Thomas et al., 2019). These adjustments will not eliminate the occurrence of cancers and will significantly alter the biology of the species, globally affecting the relationship between observed cancer statistics and defense levels due to an adaptive lag. Finally,
only in a third phase is it expected that natural selection may
favor at the species level the evolution of superior anticancer
defenses, which may eventually bring the species back into
alignment between risk and defenses. Thus, to properly test
Peto's paradox without transient effects, which are inherently
unpredictable as they depend not only on current but also
on previous conditions, it is imperative to consider species
that are in balance between their cancer risk and their can-
cer defenses. Due to anthropogenic pollution, it will become
increasingly challenging to determine which species, even
those in captivity at zoos, are aligned between their cancer
risk and anticancer defenses. Depending on the source of pol-
lution in question (e.g., in water, air, or soil) and the associated
types of cancer, it is potentially possible to make predictions
about the levels of tissue-specific resistance that will be corre-
spondingly associated.

Another scenario of particular interest for extending Peto's
paradox is where cancers lead to fewer metastases than
expected. Indeed, one of the most problematic characteris-
tics of cancers for health is their propensity to establish sec-
ondary cancerous sites, called metastases, since it is usually
the metastases, not the primary tumors, that cause the death
of patients. Blocking this process is, therefore, a crucial chal-
lenge for cancer treatment. Remarkably, there are cancers in
certain animals that have apparently been favored by natural
selection to lose the ability to metastasize within a host. These
cancers are particular forms of tumors that have become
directly transmissible, akin to true parasites, with at least
three remarkable examples: facial tumors in Tasmanian devils
(DFT1 and DFT2), and venereal tumors in dogs (CTVT) (see
Dujon et al., 2020a; Ujvari et al., 2017 for reviews). CTVT
cancer, which appeared between 4,000 and 8,500 years ago,
currently produces metastases in only 5% of cases (Ganguly
et al., 2016). Preliminary data also suggest that DFT1 can-
cer, which emerged in the 1980s, is decreasing its propensity
to metastasize (Hamede, unpublished data). Transmissible
cancers that do not metastasize allow the host to live longer
while infected, thus increasing their transmission potential.
However, the underlying mechanisms of reducing meta-
static potential are poorly understood at the moment. Future
research is needed to study the molecular pathways and
adaptations by which transmissible cancers lose their meta-
static genetic traits, providing novel insights for biomedical
research and cancer therapies. While it may seem that the sup-
pression of metastasis in transmissible cancers results from
simple mechanisms, such as the deletion of a specific path-
way like cell migration, we believe these processes are more
complex. Transmissible cancers provide unique evolutionary
models that can reveal more intricate regulatory strategies for
controlling invasive tumor cell behavior. By studying these
mechanisms, we may identify pathways that preserve cancer
viability within the host but could be exploited to curb metas-
tasis in nontransmissible human cancers. By generating novel
insights into the evolution of metastases in transmissible can-
cers, such interdisciplinary research will advance biological,
veterinary, and medical sciences.

The exploration of novel anticancer mechanisms in wild
animals should, in theory, consider species that are at an equi-
librium between cancer risks and cancer defenses (i.e., having
no or very few cancers before the post-reproductive phase).
Extending the focus of comparative cancer research beyond
Peto's paradox—and size and longevity—to encompass a
wider range of biological and ecological traits can deepen

our understanding of cancer resistance mechanisms across
species. We argue many species exhibit traits that are con-
ventionally considered prone to cancer development, such as
placentation and hormone production, yet they do not suc-
cumb to the disease. These species present valuable oppor-
tunities for understanding the intricacies of cancer resistance
mechanisms. We also argue that transmissible cancers are not
merely a scientific curiosity; they present unique opportuni-
ties to investigate how evolution can influence the metastatic
process in a natural setting and its broader implications. By
broadening our investigation to encompass such diverse traits
and species, we can uncover novel adaptive strategies evolved
by nature to mitigate cancer risk. Embracing this broader
perspective not only enhances our understanding of cancer
biology but also underscores the importance of considering a
wide array of biological and ecological factors in the pursuit
of effective anticancer strategies.

Funding

F.T. is supported by the CNRS, the Hoffmann Family and by the following grant: EVOSEXCAN project (ANR-23-CE13-0007).

*Conflict of interest:* The authors declare no conflict of interest.

Acknowledgments

We would like to express our gratitude to Carlo Maley, as
well as the two anonymous reviewers, for their valuable com-
ments and suggestions on our manuscript.

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