SYSTEMATIC REVIEW
published: 09 May 2022
doi: 10.3389/fevo.2022.861103
Cancer Susceptibility as a Cost of
Reproduction and Contributor to Life
History Evolution
Antoine M. Dujon 1,2† , Justine Boutry 1† , Sophie Tissot 1 , Jean-François Lemaître 3 ,
Amy M. Boddy 4 , Anne-Lise Gérard 1,2 , Alexandra Alvergne 5 , Audrey Arnal 1 ,
Orsolya Vincze 6,7 , Delphine Nicolas 8 , Mathieu Giraudeau 9 , Marina Telonis-Scott 2 ,
Aaron Schultz 2 , Pascal Pujol 1 , Peter A. Biro 2 , Christa Beckmann 2,10,11 ,
Rodrigo Hamede 12 , Benjamin Roche 1,13 , Beata Ujvari 2 and Frédéric Thomas 1*
1
Edited by:
Jerry Husak,
University of St. Thomas,
United States
Reviewed by:
Wendy Hood,
Auburn University, United States
Clay Cressler,
University of Nebraska–Lincoln,
United States
*Correspondence:
Frédéric Thomas
frederic.thomas2@ird.fr
† These
authors have contributed
equally to this work
Specialty section:
This article was submitted to
Behavioral and Evolutionary Ecology,
a section of the journal
Frontiers in Ecology and Evolution
Received: 24 January 2022
Accepted: 05 April 2022
Published: 09 May 2022
Citation:
Dujon AM, Boutry J, Tissot S,
Lemaître J-F, Boddy AM, Gérard A-L,
Alvergne A, Arnal A, Vincze O,
Nicolas D, Giraudeau M,
Telonis-Scott M, Schultz A, Pujol P,
Biro PA, Beckmann C, Hamede R,
Roche B, Ujvari B and Thomas F
(2022) Cancer Susceptibility as a Cost
of Reproduction and Contributor
to Life History Evolution.
Front. Ecol. Evol. 10:861103.
doi: 10.3389/fevo.2022.861103
Unité Mixte de Recherches, CREEC/CANECEV (CREES), MIVEGEC, IRD 224–CNRS 5290–Université de Montpellier,
Montpellier, France, 2 Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Geelong,
VIC, Australia, 3 CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, Université Lyon 1,
Villeurbanne, France, 4 Department of Anthropology, University of California, Santa Barbara, Santa Barbara, CA, United
States, 5 Institut des Sciences de l’Evolution de Montpellier, Université de Montpellier, Montpellier, France, 6 Institute of
Aquatic Ecology, Centre for Ecological Research, Debrecen, Hungary, 7 Evolutionary Ecology Group, Hungarian Department
of Biology and Ecology, Babes-Bolyai University, Cluj-Napoca, Romania, 8 Tour du Valat, Institut de Recherche Pour la
Conservation des Zones Humides Méditerranéennes, Arles, France, 9 LIENSs,UMR 7266 CNRS-La Rochelle Université, La
Rochelle, France, 10 School of Science, Western Sydney University, Penrith, NSW, Australia, 11 Hawkesbury Institute for the
Environment, Western Sydney University, Penrith, NSW, Australia, 12 School of Natural Sciences, University of Tasmania,
Hobart, TAS, Australia, 13 Fauna Silvestre y Animales de Laboratorio, Departamento de Etología, Facultad de Medicina
Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Mexico City, Mexico
Reproduction is one of the most energetically demanding life-history stages. As a result,
breeding individuals often experience trade-offs, where energy is diverted away from
maintenance (cell repair, immune function) toward reproduction. While it is increasingly
acknowledged that oncogenic processes are omnipresent, evolving and opportunistic
entities in the bodies of metazoans, the associations among reproductive activities,
energy expenditure, and the dynamics of malignant cells have rarely been studied.
Here, we review the diverse ways in which age-specific reproductive performance
(e.g., reproductive aging patterns) and cancer risks throughout the life course may be
linked via trade-offs or other mechanisms, as well as discuss situations where tradeoffs may not exist. We argue that the interactions between host–oncogenic processes
should play a significant role in life-history theory, and suggest some avenues for
future research.
Keywords: disease, sexual selection, reproduction, reproductive aging, neoplasia, transmissible cancer,
senescence
INTRODUCTION
Natural selection shapes organisms to maximize reproductive fitness, and this phenomenon leads
to pivotal trade-offs around which all life-history traits ultimately evolve (Williams, 1966; Rose and
Mueller, 1993; Roff, 2001; Stearns, 2006; Harshman and Zera, 2007). Exploring the consequences
of reproductive trade-offs on organisms has therefore been—and remains—a central topic in
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cancer should be a major mediator of life-history trade-offs and a
contributor to life-history evolution.
The short- and long-term fitness consequences of oncogenic
manifestations early in life, at a life-history stage where
individuals are expected to maximize their allocation of resources
toward growth and reproduction, remain poorly documented
(Vittecoq et al., 2013; Thomas et al., 2018). In addition, the
precise reasons why oncogenic processes—depending on organs,
individuals, and/or species— evolve at variable rates inside
the body are not yet well understood, although there is clear
evidence that a variety of internal and external parameters
are important (e.g., sex, age, immune status, organ ecology
and microenvironment, energetic capacity, stress, environment,
Tevfik Dorak and Karpuzoglu, 2012; Henry et al., 2015; Thomas
et al., 2016; Hochberg and Noble, 2017; DeGregori et al., 2018;
Biro et al., 2020; Vibishan and Watve, 2020). Evolutionary
ecologists have, until recently, largely neglected the importance
of cancer cells for animal ecology (Thomas et al., 2017).
There are more than 100 types of cancer (grouped into five
major categories: carcinoma, sarcoma, myeloma, leukemia, and
lymphoma) that can affect almost every part of the body
(Weinberg, 2007). In addition to malignant tumors, multicellular
organisms often harbor benign neoplasms (Boutry et al., 2022b).
Benign neoplasms have received less attention than malignant
tumors because they have less often obvious and serious impacts
on the patient/host health, even if noticeable exceptions exist (see
Boutry et al., 2022b for a recent synthesis).
Tumoral processes, especially malignant ones, can be
detrimental to host fitness by imposing direct costs on it. For
instance, malignancies affecting reproductive organs, like cervix,
uterus, endometrial, ovary or testicular cancers, can severely
compromise their host’s reproductive potential by triggering
reproductive aging or inducing infertility (Brinton et al., 2004,
2005; Paduch, 2006; Singh et al., 2011; Hanson et al., 2017).
Another well-known direct cost of (notably metastatic) cancers
on host fitness is due to their detrimental effect on survival. While
the survival cost of cancer is largely documented for human and
domestic animals, less information is available for wildlife species.
Recent studies from zoo animals showed that cancerous processes
are however widespread (see Vincze et al., 2022). The lack of
information in the wild is likely due to the fact that tumor-bearing
individuals, often in poorer condition than healthy ones, have
increased probability to die early, being victims of predation or
infections (Boutry et al., 2022a). Thus, cancer is indirectly costly
when tumor-bearing individuals are considered within their
ecosystems. Although experimental evidence would be welcome,
it is also likely that tumor-bearing individuals should be less
attractive for sexual partners, and/or will have lower ability to
deliver good parental care (Vittecoq et al., 2015).
As with other fitness-reducing factors, evolutionary theory
predicts that metazoans are under selective pressure to: (i)
avoid the source of malignancies in the first instance, (ii)
prevent tumoral progression once initiated, and finally (iii)
alleviate the fitness costs if further cancer development is not
preventable (Ujvari et al., 2016). These strategies necessarily
involve immediate and/or long-term costs that are traded against
other functions (Jacqueline et al., 2017a), even if the evolution
evolutionary biology (Schaffer, 1974; Bell, 1980; Gustafsson et al.,
1995; Hamel et al., 2010; Schwenke et al., 2016). There are
numerous examples showing that the reproductive allocation of
a given event correlates negatively with both short-term survival
and/or future reproductive performance (Stearns, 2006; Hamel
et al., 2010). Similarly, reproductive costs can be paid in the long
run, through an earlier and or steeper actuarial and reproductive
aging (Lemaître et al., 2015). Trade-offs between reproductive
effort and subsequent survival can occur for a variety of reasons,
one of them being that reproductive activities are energetically
demanding, thus the amount of energy an individual allocates
toward reproduction reduces its allocation to health maintenance
(Kirkwood, 1977; Maklakov and Immler, 2016). For instance,
reproductive activities and allocation to immune function are
often mutually constraining: increased reproductive activity
may limit immune performance, which in turn can enhance
vulnerabilities to infections (Sandland and Minchella, 2003;
French et al., 2007; Knowles et al., 2009; Fedorka, 2014; Schwenke
et al., 2016). Allocation of resources away from soma to
reproduction might also result in a decreased capacity to cope
with damage caused by stress and toxicity, and/or be associated
with detrimental by-products of metabolism, e.g., the production
of damaging reactive oxygen species (Metcalfe and Monaghan,
2013, but see Blagosklonny, 2010). Finally, some of the genes
selected for fitness conferring advantages during early life (e.g.,
increased reproductive output) may also have other functions;
for example, carrying alleles that support reproduction may
at the same time increase the risk of pathologies later in life
(i.e., antagonistic pleiotropy) (Williams, 1957; Leroi et al., 2005;
Madimenos, 2015; Austad and Hoffman, 2018; Gunten et al.,
2018).
Apart from being a leading cause of human death worldwide,
cancer is a biological process that appeared with the evolution
of metazoans during the late Precambrian (Domazet-Lošo and
Tautz, 2010; Nunney, 2013). Cancer occurs when individual
cells become malignant, i.e., lose their normal cooperative
behavior, become insensitive to host controls, proliferate in
an uncontrolled fashion, and spread from primary tumors to
surrounding tissues and then to distant organs (i.e., metastasis),
thereby causing morbidity and potentially death (Hanahan and
Weinberg, 2011). Chronological age is indisputably the most
significant risk factor (in terms of incidence) for developing
metastatic cancer, but it is also well established that oncogenic
processes frequently exist at sub-clinical levels earlier in life (in
humans and other animals, Folkman and Kalluri, 2004; Bissell
and Hines, 2011; Madsen et al., 2017), and in fact represent a
long continuum between precancerous lesions to invasive forms
(Maley et al., 2017). Recent advances in oncology suggest that
pathogens, parasites, viruses, or transposable elements may be
the most common causes of cancer in wildlife, while second-hand
smoke, nutritional challenges, breeding stress, UV radiation, and
chemicals in the environment causing somatic mutations may be
most important for pets and humans (Aktipis and Nesse, 2013;
Giraudeau et al., 2018; Pesavento et al., 2018). Since cancer is
observed in almost all branches of multicellular life, from Hydra
to whales (Leroi et al., 2003; Aktipis et al., 2015; but see Azpurua
and Seluanov, 2013; Fortunato et al., 2021), we hypothesize that
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higher fertility compared to controls (before the advent of
modern contraception) (Smith et al., 2012; see however, Oktay
et al., 2015; Daum et al., 2018). The precise mechanisms behind
this phenomenon are not completely understood, and perhaps
are simply the consequence of genetic bottlenecks. However,
they could also involve a trade-off between cancer suppression
and tolerance for invasive fetal cells (Aktipis, 2020). Placentation
in female eutherian mammals, like cancer metastasis, is indeed
an invasive process that involves the transplantation of cells into
new environments. Females in these species would therefore
be potentially more vulnerable to cancer (Kshitiz et al., 2019).
This hypothesis seems to be supported at the interspecific level,
since species of mammals with more invasive placentation such
as felines and canines are also more vulnerable to malignancies
(D’Souza and Wagner, 2014). However, Boddy et al. (2020) did
not confirm this tendency, and found instead at the interspecific
level a positive relationship exists between litter size and
prevalence of malignancy. Beyond these examples, the search
for positive selection signals on mutations occurring in cancer
suppression genes seems to be promising for the identification of
candidate genes responsible for both fertility enhancement and
cancer risk (Kang and Michalak, 2015).
The fact that cancer genes are not purged by natural selection
can also be driven by antagonistic coevolution processes that
occur in cases of conflict between evolutionary agents (Graham,
1992; Crespi and Summers, 2006). Some of these conflicts are
related to reproductive activities, e.g., parent–offspring conflict,
maternal–fetal conflict, sexual conflict, and/or sexual selection
(Haig, 2015). The genes involved in such dynamics generate
evolutionary disequilibriums, molecular-level arms races, and
tugs-of-war over cellular resources, and they may increase
susceptibility to cancer as a pleiotropic by-product of their
role(s) in antagonistic coevolution (Crespi and Summers, 2006).
Situations of sexual conflict, i.e., when the fitness of one sex comes
at the expense of the other sex, can occur when the genes involved
in rapid cell proliferations—which allow rapid growth or wound
healing—are due to sexual selection being more advantageous for
fighting males than for females. The optimum trade-off between
DNA repair and cell proliferation rate, which also relies on the
BRCA1 and BRCA2 alleles (Yoshida and Miki, 2004), is therefore
likely to vary between males and females, generating sexually
antagonistic selection. Oncogenic consequences for females, such
as breast and/or ovarian cancers, could result from a disruption of
the trade-off via a BRCA gene mutation in a somatic cell, leading
to proliferation with less-effective DNA repair. Total cancer risks
arising from perturbations to maternally and paternally opposed
growth regulation have yet to be determined (Frank and Crespi,
2011), but exploring this hypothesis with comparative analyses
seems promising. In particular, considering species that vary
in the intensity of male sexual selection relying on body size
and aggressive fights could be of interest since the differential
optimum values for the repair–proliferation trade-off between
sexes are expected to be somewhat different.
It is also thought that genes contributing to gamete production
(rate and/or quality) may use pathways that are highly beneficial
for cancer cells able to co-opt or subvert them during somatic
evolution. These pathways could allow rapid cell proliferation
of cancer defenses is predicted to be variable between species,
depending on their ecology. For instance, tumors are common
in laboratory mice, but are rarely observed in wild populations.
While this difference between natural and artificial environments
may in part be due to differences in environmental exposure
to cancer inducing agents, it also results from the fact that
the average lifespan of a wild mouse (a prey species) is only a
few months. While somatic mutations contributing to cancer in
laboratory mice may be common, historically, there may have
been little selection on immune processes that prevent, or slow
cancer because wild mice rarely live long enough to experience
tumor formation (Perret et al., 2020).
Thus, cancerous processes, through their direct costs on hosts
and/or most often through the costs of host defenses, have the
potential to impose life history tradeoffs (Aktipis et al., 2013;
Brown and Aktipis, 2015; Muller, 2017). We discuss here the idea
that malignant processes are crucial to consider when studying
life-history traits because malignant dynamics—and hence their
consequences on health and survival—are likely to be linked
in multiple ways with the age-specific reproductive activities of
organisms (see Figure 1). While there have been many review
papers linking host evolutionary ecology to cancer (e.g., Peto’s
paradox), to our knowledge, our paper is the first to primarily
focus on the associations between cancer and reproduction.
This synthesis highlights the underestimated role of oncogenic
processes in shaping the multiple facets of the age-specific
reproductive biology of multicellular hosts.
GENES PROMOTING BOTH FERTILITY
AND CANCER RISK
One mechanism that can link together reproduction with
increased susceptibility to cancer is through genes that have
direct effects on both. Like several other biological processes
detrimental to health, malignant dynamics can also be embedded
in the antagonistic pleiotropy theory (e.g., Crespi and Summers,
2006; Carter and Nguyen, 2011; Jacqueline et al., 2017a; Lemaître
et al., 2020a). At the genetic level, for instance, some alleles that
increase cancer risk as a secondary effect of their positive roles on
reproductive success have been identified; a good example is the
Xmrk melanoma-promoting oncogene in the fish Xiphophorus
cortezi (Figure 2). Despite significant deleterious cancer-induced
effects leading to a shorter lifespan, this oncogenic allele
persists in natural populations presumably because it is also
associated with a larger body size, which increases the individual’s
reproductive success through mate competition. This oncogene
is also directly correlated with aggressive behaviors (Fernandez,
2010). In addition, the presence of melanoma on the male’s caudal
fin intensifies the spotted caudal melanin pattern, which increases
female preference for these mates (Fernandez and Morris, 2008;
Summers and Crespi, 2010).
Another example concerns mutations on the tumorsuppressing gene BRCA, which is responsible for DNA repair.
While women carrying BRCA1/2 mutations have higher cancer
incidence and higher mortality, one study reported that BRCA
mutation carriers born in Utah prior to 1930 had naturally
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FIGURE 1 | Plan of this synthesis: malignant processes and then consequences on health and survival are linked in multiple ways with the age-specific reproductive
activities of organisms.
FIGURE 2 | Antagonistic pleiotropy and oncogenic congenital mutations: the Xmrk melanoma-promoting oncogene in the fish Xiphophorus cortezi. Sexual selection
processes may sometimes favor cancer promoting oncogene alleles, as this is observed in the fish Xiphophorus developing melanoma (bottom Photo). Despite
shorter lifespan due to the deleterious cancer-induced effects, the oncogenic Xmrk allele is not eliminated from natural populations of Xiphophorus, because several
associated benefits early in life outweigh late costs (i.e., antagonistic pleiotropy). Xmrk allele is indeed associated to a larger body size and higher aggression, which
increases individual’s reproductive success through mate choice and competition for mates. The source and credit for the fish photos: Johnny Jensen (up) and
Andre Fernandez (down). Figure modified from Fernandez and Morris (2008). *P < 0.05, **P < 0.01.
and/or avoidance of control by tumor suppressors or the immune
system (Crespi and Summers, 2006). For example, SPANX genes
in primates, which show evidence of strong positive selection, are
involved both in spermatogenesis and in melanoma progression
by promoting cancer cell growth (Kleene, 2005). More recent
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studies also support the hypothesis that some genetic pathways
of spermatogenesis, whose evolution is governed by responses
to sexual selection and intra-sexual conflict, are the same
as those used by cancer cells to increase their survival and
replication (genes such as BRIP1, BUB1B, KTN1, and RANBP2)
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telomere dynamics could also occupy a pivotal position in
these processes. Indeed, allocation toward the maintenance of
costly sexual signals often alters oxidative metabolism (Hill,
2014), which can, in turn, provoke telomere erosion (Monaghan
and Ozanne, 2018) and influence the emergence of oncogenic
mutations. It is predicted that natural selection should favor
the expression of secondary sexual traits over the cost of
telomere dysfunction until the organism reaches its maximum
reproductive potential, even if this is likely to promote malignant
progressions beyond this (Taff and Freeman-Gallant, 2017; Pepke
and Eisenberg, 2021). In a recent study, Wang et al. (2019)
studied the genetic basis of antler regeneration in ruminants;
antlers are among the fastest-growing bone in the animal
kingdom. In red deer (Cervus elaphus), for instance, antlers
regrow annually and reach up to 30 kg, with growth rates
of ∼1.7 cm/day, which necessitates a rate of cell proliferation
that surpasses classical cancerous tissue growth. Wang et al.
(2019) found that the genes underlying the expression of these
large sexual ornaments are among those that both promote
and suppress cancer (Figure 3). Specifically, there was a higher
correlation between the gene expression profiles of antlers and
bone cancer such as osteosarcoma than between those of antlers
and normal bone tissues, suggesting that antler growth and
oncogenesis rely on similar developmental programs. Cancer is
typically a pathology arising from perturbations to a precarious
balance between strongly opposed growth promoters and growth
repressors (Aktipis, 2020). However, these authors discovered
that contrary to the situation in osteosarcoma, where neoplasms
progress unchecked, antler growth was tightly regulated by the
activity of cancer-controlling genes (both tumor-suppressing and
tumor-growth-inhibiting genes), suggesting that antler growth is
mechanistically equivalent to a controlled form of bone cancer
growth. Cervids generally display a very low risk of cancer
(Vincze et al., 2022). Ideally, the same genes promoting cancer
prevention (tumor-suppressors like BRCA, TP53, BUB1, BUBR1,
TGF-βRII, Axin, DPC4, p300, and PPARγ which generally play a
role in controlling the cell cycle or DNA repair) would be selected
for and likely conserved. However, they would share the same
pathway used by cancerous cells because the same genes are used
in cell division. Given that antlers are lost every year, we might
speculate that this could potentially be a defense mechanism.
In line with this hypothesis, a recent comparative analyses of
cancer risk across almost 200 species of mammals highlighted
that Artiodacyla such as Cervids are much less prone to cancer
than other mammalian orders (Vincze et al., 2022).
The apparent lack of a correlation between sexual ornament
size and cancer rate may be explained by mechanisms that offset
the increased cancer risk. As possible supportive evidence, albeit
in a different ecological context, Thomas et al. (2020) argued
that strong ongoing artificial selection in domestic animals has
sometimes resulted in extreme phenotypic responses favoring a
higher incidence of cancer. However, there is also evidence for
effective anti-cancer defenses in several domesticated animals,
suggesting that artificial selection may also favor the evolution
of compensatory anticancer defenses (see also Ibrahim-Hashim
et al., 2020). More research in wild species, especially at the
intraspecific level, would be necessary to evaluate how robust and
(Vicens and Posada, 2018). It has also been suggested that the
CAG repeat region of the androgen receptor could be a locus
of antagonistic pleiotropy in the context of sexual selection and
sexual conflict (Summers and Crespi, 2008). Short repeats are
associated with increased fertility at the phenotypic level, but
there is also evidence that somatic evolution of malignant cell
lineages during cancer progression are often associated with
a repeated pattern of shortening of the CAG repeat, a priori
because of positive selection among cell lineages.
AGE-SPECIFIC REPRODUCTIVE
PERFORMANCE AND CANCER RISK
Intra-Sexual Selection
As mentioned before, antagonistic pleiotropy is when one gene
has opposite effects on fitness at different ages, such that their
effects are beneficial in early life, when natural selection is
strong, but harmful at later ages, when selection weakens.
In a theoretical study, Boddy et al. (2015) investigated the
possible links between cancer risks and the level of intraspecific
competition, assuming that an underlying resource-based tradeoff between competitiveness and allocation into cancer defenses
exists. As has been empirically observed (see Clocchiatti et al.,
2016 for an example in humans), the model first showed that
cancer prevalence is expected to be lower in females than in
males, since mating competition usually has greater reproductive
payoffs for males than for females (Clutton-Brock and Vincent,
1991) and also because of the immune-enhancing effect of
estrogen (Taneja, 2018; even if the picture is more variable
in humans, Mulder and Ross, 2019). Although experimental
evidence is currently lacking, the higher male susceptibility is
likely to be exacerbated when they grow faster and/or have to
develop and maintain extravagant secondary sexual traits. This
should theoretically be the case because the required higher
cell proliferation itself increases cancer risk (especially in body
areas with the greatest cellular divisions, e.g., testes cancer,
antleromas). For instance, the insulin/insulin-like growth factor
(IGF) signaling pathway to mTOR is essential for the survival
and growth of normal cells but also contributes to the genesis
and progression of cancer, increasing cell proliferation and antiapoptosis processes (LeRoith and Roberts, 2003; Floyd et al.,
2007). Another reason is because of a diversion of resources from
somatic maintenance (e.g., DNA repair or immune defenses).
A potential self-maintenance mechanism suffering shortfall could
be the antioxidant machinery, when strenuous activity (e.g.,
mating competition, reproductive effort, maintenance of costly
sexual signals) leads to an increased production of reactive
oxygen species causing oxidative stress. Even if empirical data
have not been always consistent, oxidative stress has been viewed
as an important physiological costs of reproduction (Blount et al.,
2016; Pap et al., 2018) and it is well known to participate in cancer
development by promoting cancer initiation and progression
through induced DNA damage, leading to mutagenesis, and
by affecting DNA methylation patterns or the expression of
oncogenes (Van Remmen et al., 2004; Kreuz and Fischle, 2016).
Moreover, as recently highlighted by Ujvari et al. (in press),
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FIGURE 3 | Antler regeneration, neurogenesis and oncogenesis pathways. (A) Annual antler regeneration cycle in red deer. Antlers, after shed in winter regenerate in
spring, and then grow most rapidly in summer. In autumn, they calcify and shed their velvet. For (B) (Axon guidance pathways) and (C) (Oncongenesis pathways):
blue, genes positively selected in cervids; yellow, cervid-specific HCE associated genes; green, antler-specific expression genes. (D) Antler anatomy. (C) The
anatomy of the antler. The source and credit for the red deer: Pixabay. Figure modified from Wang et al. (2019).
because of the sexual selection benefits associated with height in
males (Stulp et al., 2013) as well as the reduced risks of obstetric
complications in females (Guégan et al., 2000), and also because
most oncogenic consequences will occur relatively late in life.
However, such processes, at least in wild species, could result
in positive feedback cycles in oncogene evolution, leading to
improved tumor suppression, greater developmental precision
and complexity, and further adaptive changes driving pleiotropic
oncogene evolution (Crespi and Summers, 2006). Domestication
of animals by humans may provide some support for the
hypothesis that a mismatch between cancer risk and cancer
defenses may promote malignant proliferation. For example, the
artificial selection for size in dogs results in higher incidences of
bone cancer in larger breeds compared to smaller ones (Grabovac
et al., 2020) because selection for genes responsible for height
(and hence a larger number of cells) was not accompanied by
selection for more efficient cancer defenses (Thomas et al., 2020).
In a related vein, pediatric cancers in humans most often concern
three compartments, brain, blood and bone, that have undergone
buffered these compensatory protections are. Indeed, because
sexual selection processes may be intense in natural populations
depending on the ecological contexts, it could be expected
that animals benefiting from abundant resources might develop
secondary sexual traits whose expression level is higher than
that corresponding to their cancer defenses. A rapid evolution
in this direction would then drive genotypes away from the
optimum, which would result in an increased risk of cancer,
at least until the species or population adapts to the changes
(Abegglen et al., 2015; Boutry et al., 2020). Such kind of
mismatch scenario could potentially be investigated in habitat
when wildlife artificially benefits from excessive quantity of food.
In humans, it is well established that good nutrition has promoted
growth in recent decades, allowing individuals to grow taller
(Grasgruber et al., 2014). However, it is also known that cancer
risk increases with adult height, at least in part because the
number of cells correlates positively with stature, while cancer
defenses apparently remain the same (Nunney, 2018). It is
unlikely that mechanisms will evolve to prevent large stature
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rapid phenotypic changes in their developmental trajectories
along the human lineage (Leroi et al., 2003). In current times,
the risk of mismatch can also be exacerbated because anthropic
activities result in higher pollution by mutagenic substances in
ecosystems (Giraudeau et al., 2018) that—all things being equal—
lead to unprecedented risks of cell derailment rates in organs that
undergo intense cell divisions.
Although potentially specific to certain populations (see
for instance Trumble et al., 2014), testosterone in males has
frequently been associated not only with a greater investment
in mating behavior (Wingfield et al., 1990; Peters et al., 2008;
Summers and Crespi, 2008; Dixson, 2015), but also (although
still debated, Michaud et al., 2015) with a higher risk of prostate
cancer (e.g., Alvarado, 2013 for males in human polygynous
societies). This correlation potentially supports the hypothesis
of a trade-off, where higher testosterone levels would allow
males to engage in more short-term mating with different
partners but at the cost of a higher long-term risk of prostate
cancer. It is however, difficult to separate hormonal effects and
higher exposure to sexually transmitted carcinogenic viruses
also affecting prostate tissues, a risk that increases with the
number of sexual partners (e.g., Moghoofei et al., 2019). Further
research is needed to decipher the interactions between sexual
hormones, the immune system, and cancer development in wild
species. Promising models could be social species, especially
those for which there are differential hormone levels and
cancer risks between dominant and subordinate individuals
(Jacqueline et al., 2017a).
Inter-Sexual Selection
In addition to intra-sexual selection, inter-sexual selection
through mate choice is central in the theory of sexual selection
(Andersson and Simmons, 2006). For many years, it was expected
females of many species chose to mate with old rather than young
males, because older males often provide better resources (e.g.,
territories, parental care) and/or pass good genes on to their
offspring (Brooks and Kemp, 2001). However, these theoretical
predictions are now thoroughly revisited in the light of recent
studies demonstrating the under-estimated occurrence of male
reproductive aging, as well as the detrimental consequences of
this process on female fitness (Lemaître and Gaillard, 2017;
Monaghan and Metcalfe, 2019; Monaghan et al., 2020; Segami
et al., 2021). Empirical studies suggest that female preference
toward young males could be a pervasive mating tactic in the
living world (e.g., Verburgt et al., 2011; Vanpé et al., 2019).
Here, we propose that mating preferentially with younger males
might also be adaptive in terms of a decreased cancer risk in
the progeny. One reason is that males accumulate deleterious
mutations in their germ-line at an ever-increasing rate as they
age (Beck and Promislow, 2007), thereby reducing the quality
of genes passed on to the next generation, which potentially
favors cancer (e.g., see Choi et al., 2005 for an example that
older paternal age increases the risk of breast cancer in female
offspring). In addition, in several species – at least in humans
and chimpanzees – sperm telomere length is positively correlated
with male age, leading to a positive correlation between paternal
age at conception and offspring telomere length (Eisenberg
and Kuzawa, 2018; Eisenberg, 2019; Eisenberg et al., 2019).
Longer telomeres in descendants of old fathers are likely to
predispose the novel generation to a higher risk of cancer since
cells have a greater chance to accumulate bad mutations before
replicative senescence occurs and eliminates them (e.g., Aviv
et al., 2017). Theoretical models aiming to predict age-based
mating preferences in females based on the benefits-costs balance
provided by both young and old partners should now fully
consider the risk of cancer in the progeny. For instance, it may
remain evolutionarily beneficial for females to produce a progeny
whose lifespan will be shortened by cancer in species where old
males provide more resources, especially if the cancer-induced
death can occur relatively late in the life of offspring (i.e., once
most of their reproduction has been achieved). In addition, given
the heritability of height (Yang et al., 2010), further studies should
also explore the possible oncogenic consequences for tall partner
preference in humans.
Individual ‘Quality’ as a Means to
Explain Situations Where Trade-Offs
Seem Absent
Although trade-offs between reproduction and the ability to
ward off cancer are expected based on long-standing life
history theory (citations above), we should not always expect
that reproductive costs are evident or detected. For example,
investment into large antlers by Artiodactyla (discussed above)
may not create detectible energy trade-offs and increased cancer
risk if dominant individuals monopolize resources prior to
breeding as is often the case in some species. That is, some
individuals of high ‘quality’ possess abundant energetic resources
that permit them to allocate energy to competing demands
obscuring trade-offs. Similarly, some of the dramatic anticancer adaptations found in domestic animals (Thomas et al.,
2020) may be also explained by the fact that abundant food
permits simultaneous allocation of energy to reproduction and
anti-cancer functions, again obscuring trade-offs. These views
are consistent with theory showing that when variation in
energy acquisition among individuals is greater than variation
in allocation within individuals, competing life history traits
will no longer be negatively correlated among individuals
(van Noordwijk and de Jong, 1986). Indeed, reviews show
energy expenditure on activity, reproduction and maintenance
metabolism can often be positively correlated at the among
individual level for domestic and laboratory reared animals
(Biro and Stamps, 2008, 2010).
Frontiers in Ecology and Evolution | www.frontiersin.org
Gestation, Brood Size, and Parental Care
In numerous species, reproduction is costly for females in terms
of energy, nutrients, and metabolic adjustments, which may lead
to faster aging and reduced longevity when reproductive effort
increases (Westendorp and Kirkwood, 1998; Lemaître et al.,
2015; Jasienska, 2020). Physiological consequences of elevated
reproductive expenditure are also observed on biological markers
of aging. For instance, in species for which males also have a
high allocation of resources toward parental care, e.g., common
terns (Sterna hirundo), where males are primarily responsible
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small numbers of fertile eggs during a limited period of the year,
strong artificial selection leading to the domesticated jungle fowl
hen (Gallus gallus domesticus) has resulted in animals with a short
lifespan and prolific daily ovulation and egg laying. Malignant
ovarian cancer in domesticated chickens is frequent, but there is a
five-fold variability between strains in the incidence of the disease
(Johnson and Giles, 2006), suggesting that anticancer responses
may have subsequently evolved in certain strains. Similarly, in
dairy cows and goats that have been selectively bred for mammary
gland growth and milk production, there is paradoxically a
low occurrence of mammary tumors compared to domestic
carnivores (Munson and Moresco, 2007), suggesting once again
that anticancer mechanisms compensating for increased risks
of lobular alveolar growth and hence malignancies have been
concomitantly and/or subsequently selected. Further studies
would be necessary to explore how relevant these phenomena
are in wild species currently experiencing alterations in the
reproductive biology because of climate change (e.g., Winkler
et al., 2002; Pankhurst and Munday, 2011).
for chick feeding, a negative association between reproductive
success and telomere length is observed only in males (Bauch
et al., 2016). The direct and/or indirect consequences of these
kinds of reproductive costs on oncogenic process dynamics
have not yet been fully explored for most species. Pregnancy in
women, at least in Western populations, seems to have a dual
effect on breast cancer risk (Hsieh et al., 1994). While full-term
pregnancies in early life (<30 years) reduce breast cancer risk
in the long-term (Albrektsen et al., 2005; Hurt et al., 2006), in
the short term they boost the development of oncogene-activated
cells into tumors and/or promote a metastatic cascade (Lambe
et al., 2002; Lyons et al., 2011), which transiently increases
cancer risk. The most common oncogenic progressions observed
during pregnancy are malignant melanoma and lymphomas,
leukemia, and breast, ovary, cervix, colon, and thyroid cancers
(Pavlidis, 2002; Oduncu et al., 2003). The cancer risk is highest
within the first 5 years after giving birth, and the risk of
breast cancer in parous women is increased for more than 15–
20 years compared with nulliparous women (Nichols et al., 2019).
Multiple factors are likely responsible for this higher vulnerability
to cancer during pregnancy, such as the strategic modulation of
the maternal adaptive immune system during the first trimester
and a relatively high inflammatory status (Fessler, 2002; Abrams
and Miller, 2011; Lyons et al., 2011; but see Hové et al.,
2021). The pathophysiology of cancer associated with pregnancy
also includes factors like hormonal changes, permeability, and
vascularization (D’Souza and Wagner, 2014; Hepner et al., 2019).
Enhanced reproductive effort through increased parental
care has often been linked to concomitant or subsequent
reduced immune-competence (Nordling et al., 1998), which
in return should promote the proliferation of malignant cells
(Jacqueline et al., 2017a). However, it seems likely in nature that
reduced immunocompetence would first increase the frequency
of infections that are detrimental to survival in the short term,
long before malignant processes that escape immune-surveillance
could have an effect of survival. The fact that detrimental
oncogenic consequences in the wild are hidden because of deaths
resulting from infectious processes does not mean that they are
not significant, nor can we exclude the possibility that oncogenic
consequences may interact with infectious dynamics (e.g., see
Goldszmid et al., 2014; Jacqueline et al., 2017b, 2020). The
oncogenic consequences resulting from trade-offs with enhanced
parental care, if any, will be mainly observed in parasite- and
predator-free environments such as zoos, provided breeding
activities continue (see also Tanaka et al., 2020).
While high reproductive investments can potentially result
in increased cancer risks for individuals due to immediate
trade-offs, it is also expected that natural selection can fix
these problems on the long term. For instance, Brown and
Aktipis (2015) suggested in a theoretical study that in cases of
extended parental care, as well as with cooperative breeding
systems, selection can favor cancer suppression into old age.
At least for the proof of concept, artificial selection in the
context of domestication illustrates that enlarging reproductive
efforts may select for compensatory adaptations or additional
defenses (Thomas et al., 2020). For example, while the ancestor
of domesticated hens may live for 20–30 years and produce only
Frontiers in Ecology and Evolution | www.frontiersin.org
Reproductive Aging
The evolutionary ecology literature is replete of studies
documenting reproductive aging (i.e., the decline in reproductive
performance with increasing age, also coined reproductive aging)
in females (see Holmes et al., 2003; Lemaître and Gaillard, 2017
for reviews). The decline in litter size from 10 years of age onward
observed in Alpine marmot, Marmota marmota (Berger et al.,
2015) constitutes one of the numerous examples of reproductive
aging, and many other of reproductive traits (e.g., litter size,
birth rate, juvenile survival) have been show to decrease with
age. Nowadays, the common view is that female’s reproductive
aging is the rule rather than the exception, at least in endotherm
vertebrates (more than 60% of the studies species in both birds,
Vágási et al., 2021 and mammals, Lemaître et al., 2020b) even
if reproductive aging trajectories remain highly variables both
within and across species (Reid et al., 2010; Lemaître et al.,
2020b). Reproductive aging is obviously particularly pronounced
in species displaying menopause (see Péron et al., 2019), a
cessation of the reproductive functions that occurs many years
before death. In addition, there is now pervasive evidence that
reproductive aging is common among males of various species.
Indeed, while evidence that male fertilization efficiency decreases
with age have been documented for a long time in human
(see Johnson et al., 2015) and laboratory rodents (vom Saal
et al., 1994), an increasing number of studies are now reporting
male reproductive aging in semi-captive or wild populations of
animals. Such decline in reproductive performance have been
observed using reproductive success metrics (e.g., mating success,
Raveh et al., 2010) but also the conspicuousness of secondary
sexual traits (e.g., Perrot et al., 2016, or the quality of the
ejaculates, Preston et al., 2011). However, while the study of
reproductive aging is showing an unprecedent infatuation, the
link between both reproductive aging and oncogenic processes
are yet to be deciphered.
These two processes, reproductive aging and oncogenic
processes, can share similar proximate origins. As emphasized
in the sections above, an elevated reproductive expenditure
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than daughters (Bérubé et al., 1996; Whittingham and Dunn,
2000; Gibson and Mace, 2003; Cameron-MacMillan et al., 2007;
Rickard et al., 2007). If male embryos more strongly foster the
proliferation of existing malignant cells during pregnancy than
female embryos, it could be expected that a sex ratio biased in
favor of male progeny could, all else being equal, result in a higher
overall maternal cancer risk and/or a higher risk of cancer at a
younger age. The literature on this topic remains controversial at
the moment (e.g., Hsieh et al., 1999; Wohlfahrt and Melbye, 2000;
Saadat, 2010).
In addition, it would be particularly relevant to explore
whether some of the mammalian species that show no decline
in pregnancy rates with increasing age (e.g., white taileddeer, Odocoileus virginianus) (DelGiudice et al., 2007) display a
higher risk of cancers or have evolved alternative anti-defenses
mechanisms to buffer cancer risk. This approach would also be
relevant in ectotherm species that often show no decline (or
sometimes even an increase) in fertility with age (e.g., Cayuela
et al., 2020). Many studies are currently seeking to identify the
biological properties enabling many ectotherm species to escape
aging (e.g., Hoekstra et al., 2020 in reptiles). It has been notably
highlighted that telomere dynamics can be particularly variable in
these species (Hoekstra et al., 2020) with an absence of decline in
telomere length with age (e.g., Ujvari and Madsen, 2009 in water
python, Liasis fuscus). Whether this maintenance of telomere
length with age is due to an increased expression of telomerase,
which would in turn increased cancer risk is yet to be explored
(Olsson et al., 2018) but would constitute a key support for a
trade-off between the intensity of reproductive aging and the
risk of cancer. Albeit limited, the bunch of empirical evidence
compiled so far highlights that the risk of cancer is far from being
negligible in ectothermic species such as reptiles (Madsen et al.,
2017) which suggest that embracing this research path might be
full of promises.
could be responsible for an increased risk of cancer (Boddy
et al., 2015). Interestingly, there is compelling evidence that such
substantial allocation to reproduction during early-life is also
detrimental in terms of an earlier/stronger reproductive aging
(e.g., Nussey et al., 2006 and Lemaître et al., 2014, for examples
in females and males red deer, Cervus elaphus, respectively) and
the physiological pathways that have been suggested to mediate
the link between early- and late-life reproductive performance
are strikingly similar to the one suggested to be involved in
the reproductive effort-cancer trade-offs (e.g., oxidative stress,
telomere attrition, see Kalmbach et al., 2015). However, this does
not preclude any complex interactions between reproductive
aging and oncogenic processes and understanding whether the
occurrence of cancer is a cause, a consequence or is – to some
extent – independent to the aging process remains a longstanding question (de Maghalaes, 2013; Thomas et al., 2018).
Moreover, it is noteworthy that the cancer-reproductive aging
dynamic is likely to be different between males and females for
which the age-specific cancer rate of reproductive organs show
striking differences (see de Maghalaes, 2013).
The various risk of cancers associated to the physiological
pathways modulating the reproductive sequence (e.g., pregnancy
in mammals) might have constituted a selected pressure on the
evolution of reproductive aging patterns. For instance, it has
recently been proposed (Thomas et al., 2019a) that menopause
in humans (and in a few cetaceans) may have specifically evolved
as an anticancer adaptation for some mismatches between
the dynamics of oncogenic processes and natural anticancer
adaptations that have occurred during recent evolutionary
changes (Figure 4). While it is a natural phenomenon that
oncogenic processes steadily accumulate in the body with age,
pregnancies are unlikely to initiate cancers in an evolutionary
stable context. However, mismatches in cancer defense levels
can cause oncogenic processes to accumulate at higher rates,
enhancing the growth of existing tumors and raising the risk
of tipping the balance toward the initiation of uncontrollable
metastatic cancers. Thus, after a given age, pregnancy could be
associated with a higher probability of premature death due
to metastatic cancers. The physiology of fertile women itself is
also expected to favor malignant progression because several
cancers also depend on hormones (estrogen and progesterone)
for their growth (Aktipis et al., 2015; Aktipis, 2016; Atashgaran
et al., 2016). Menopause could potentially have evolved as a
“natural hormonal therapy” to prevent or alleviate the growth
of malignancies before a fatal threshold is reached (Thomas
et al., 2019a). If reproduction can contribute to an increase
in oncogenic processes later in life, it is however, not the
only nor even the most important contributor, and cancers
remain common even after menopause and/or in nulliparous
women (Gleicher, 2013; Einstein et al., 2015). This emphasizes
how cancers must be viewed within multivariate life-history
strategies and tradeoffs.
From this hypothesis, further fascinating directions (still
debated in humans, e.g., Saadat, 2010) remain to be explored,
such as the influence of offspring sex ratio on cancer risk, for
example. All else being equal, sons in sexually dimorphic and
polygynous species are often more costly to produce or rear
Frontiers in Ecology and Evolution | www.frontiersin.org
TRANSMISSIBLE CANCERS AND
CANCERS WITH AN INFECTIOUS
CAUSATION
At least for dogs and Tasmanian devils, infection by transmissible
malignant cells can be viewed as a cost of reproduction.
In the vast majority of cases, cancer is not a contagious
disease and malignant cells die with their host. However, in
at least nine independent cases, cancer cells have evolved the
capacity to be horizontally transmitted: one cancer in dogs,
two in Tasmanian devils (Sarcophilus harrisii), and seven in
bivalve species (McCallum et al., 2009; Yonemitsu et al., 2019;
Dujon et al., 2020; Garcia-Souto et al., 2022). In dogs, canine
transmissible venereal tumor (CTVT) is indeed caused by a
sexually transmitted cancer cell line that affects dogs worldwide
(Strakova and Murchison, 2014). The tumors are usually localized
on the external genitalia (penis and foreskin in males and vulva
in females), and it spreads between individuals through sexual
intercourse and licking and/or biting the affected areas. These
transmissible cell lines appeared between 8,000 and 11,000 years
ago (Strakova and Murchison, 2015; Ostrander et al., 2016).
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FIGURE 4 | Menopause as a possible (transient) adaptation to cancer risk following an evolutionary mismatch. (A) When cancer defenses are in alignment with
malignant risks, oncogenic processes slowly accumulate through time, and even if pregnancy periods exacerbate their dynamics, the risk of metastatic cancers
remains low. (B) Following an ecological and/or evolutionary mismatch, cancer defenses may become too weak given the novel cancer risks. Oncogenic processes
accumulate rapidly, and this time reproductive episodes exacerbate metastatic cancer risks sooner in life for females, resulting in a short lifespan and a low fitness.
From this situation, two evolutionary outcomes are possible, natural selection can (i) favor the evolution of better cancer defenses in these species (i.e., as in large
animals such as whales and elephants), coming back to a situation comparable to (A), here (C), or (ii) favor females ceasing their reproduction prematurely to
preserve their health and invest their energy/resources for their grandchildren (D). In this later situation, female’s fitness is higher than in (B) because of inclusive
fitness. The (D) scenario could in theory be just a transient situation until other cancer defenses are selected (A,C examples). Figure modified from Thomas et al.
(2019a).
both induce large ulcerating tumors around the face and jaws,
and DFT2 neoplasms are also frequently found in other parts of
the body (James et al., 2019). DFTD, for which there is now a lot
of information, is clearly fatal, with death usually occurring 9–
12 months after the appearance of the first lesions with evidence
of some individuals surviving up to 2 years (Wells et al., 2019).
In only 25 years, the demographic cost of this transmissible
cancer has been devastating, posing a serious conservation threat
to the species, which is now classified as “Endangered” by the
International Union for Conservation of Nature (Hawkins et al.,
2008). While natural selection for less aggressive phenotypes
could be expected in devils on the long term, it has not yet been
observed, presumably because aggression is a trait associated
with increased mating and breeding success in this species
(Hamede et al., 2013). In evolutionary terms, it remains more
Presumably as the result of this relatively long co-evolution
with its hosts, CTVT rarely metastasizes and even displays a
regressive stage (Das and Das, 2000; Martincorena et al., 2017).
In Tasmanian devils, malignant cells are responsible for two
cancers called devil facial tumor disease (DFTD), and devil
facial tumor 2 (DFT2). It is not directly sexually transmitted,
rather direct contact through biting is required, which frequently
occurs during social interactions linked to reproduction. Infected
individuals can still mate but they have reduced survival as
a consequence of mating. DFTD was discovered in 1996 in
northeastern Tasmania and has evolved into at least five clades
(Hawkins et al., 2006; Kwon et al., 2020), whereas the second
and independently emerged cancer, DFT2, was discovered in
southeastern Tasmania at the d’Entrecasteaux Peninsula in 2014;
(Pye et al., 2016; James et al., 2019; Figure 5). DFTD and DFT2
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FIGURE 5 | Transmissible cancers in Tasmanian devils. Tasmanian devils with DFTD and DFT2 and the respective tumor karyotypes. Red arrows indicate
chromosomes carrying cytogenetic abnormalities. The four marker chromosomes found in DFTD are labeled M1 to M4. Karyotypes from Pye et al. (2016).
FIGURE 6 | Tumors in Hydra oligactis. (A) Non-tumorous and tumorous hydra. Neoplasia not only severely alter the polyp’s body shape, but tumor-bearing
individuals also show a shift in their microbiota and display a higher number of tentacles (Domazet-Lošo et al., 2014; Rathje et al., 2020). (B) Vertical transmission of
tumoral cells in Hydra oligactis. After emergence, buds from tumorous hydra are morphologically similar to non-tumorous hydra, but after 4–6 weeks, they develop
tumors as their parental polyp (Photo Justine Boutry).
monozygotic twin have been shown to transmit to the cotwin via intraplacental anastomoses (Clarkson and Boyse, 1971;
Greaves et al., 2003). In the basal metazoan hydra (Hydra
oligactis), tumor-bearing individuals (Figure 6) directly transmit
tumoral cells to their offspring when reproducing asexually via
budding (Domazet-Lošo et al., 2014). Given the omnipresence
of oncogenic processes in multicellular organisms as well as the
fact that transmissible cancer cells can have dramatic effects
on their host’s fitness (e.g., Tasmanian devils), Thomas et al.
(2019b) argued that sexual reproduction may have been favored
by natural selection over evolutionary time as a radical way to
prevent the vertical transmission of cancer cells, since it allows
beneficial to reproduce at a cost of developing and dying from
DFTD than to remain healthy without reproducing. Interestingly,
there is increasing evidence of tumor regressions in the wild,
suggesting that devils are adapting to DFTD (Margres et al., 2018,
2020), and that a coexistence of devils and this transmissible
cancer may be a long-term enzootic outcome (Wells et al., 2019;
Hamede et al., 2020).
Reproduction can also be an opportunity for tumor cells to be
vertically transmitted, from parent to offspring. Although rare,
transmissions of cancer cells have been observed in humans
from mother to fetus (Isoda et al., 2009; Greaves and Hughes,
2018). In addition, neoplastic leukemia cells arising in one
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fetus during pregnancy and/or by choosing taller men as
sexual partners.
(4) Finally, we also need to understand over the long term
how these interactions may trigger the evolution of defense
mechanisms that prevent and/or alleviate the detrimental
effects of malignant cells on the fitness of breeding
animals. Whether the directionality of the relationship
between reproduction and cancer varies among individuals,
populations, or species is poorly understood, but should
be explored given that cancer dynamics can sometimes
influence reproductive decisions, as is the case in Drosophila
(see above sections). Research programs addressing these
questions are particularly timely since modifications of
environmental conditions by human activities have been
associated with both alterations in the reproduction
biology and increased cancer rates in wild populations.
A better understanding of the dynamic interplay between
age-specific reproductive activity and the dynamics of
oncogenic processes remains a major goal for diverse
research areas such as population dynamics, conservation
biology, epidemiology, and public health.
the offspring’s immune system to be more efficient at recognizing
and eliminating these cells [but see also Aubier et al. (2020)].
In addition to transmissible malignant cells, several cancers
have an infectious causation, and a considerable proportion are
transmitted during some step related to reproductive activity.
Indeed, pathogens that have been recognized as etiological
agents of cancers (e.g., herpes simplex viruses, cytomegalovirus,
hepatitis virus, papilloma viruses, human immunodeficiency
virus, Eskinazi, 1987) are usually transmitted by genital contact or
intimate kissing (Ewald, 2009). For this category of malignancies,
cancer risk is not surprisingly associated with increased sexual
activity (e.g., Bosch et al., 1996; Hayes et al., 2000; Cooper et al.,
2007; Gómez and Santos, 2007).
CONCLUSION
(1) Reproduction is a central activity for all living organisms,
and is also associated with a diversity of costs that need
to be considered for a full understanding of the selective
landscape in which organisms live and evolve. While
decades of research have focused on the identification
and implications of these costs, little attention has been
devoted to exploring how the schedule of reproductive
activities over the life course may also influence malignant
cell dynamics and cancer defenses that in turn affect
health and survival.
(2) Most ecologists currently consider that reproductive events
have little or no impact on oncogenic processes, but
this has yet to be properly studied. One must also
consider separately the trade-offs that are optimal in a
Darwinian logic maximizing reproductive success, from
those that are relevant in a public health perspective, for
which disease risks occurring after the reproductive period
matter too. Further studies would need to explore not
only whether there are connections between reproductive
costs and the dynamics of malignant processes, but also
determine for different species and organs the “shape” of the
relationship through time (e.g., linear, exponential, steps
with thresholds).
(3) In addition, we need to improve our understanding
of the potential interactions between different active
evolutionary processes. We can consider birth weight as
an example for which it has been established that high
values are associated with higher cancer rates later in
life. In humans, at least in the past, higher birth weights
and/or size have been associated with fitness benefits,
especially survival early in life under a wide range of
environmental conditions. Certain genes could therefore
mediate antagonistic pleiotropy, which is associated with
the selection for enhanced birth weight due to survival
benefits early in life at the expense of the later increased
risk of cancer. Because of the same fitness benefits, this
phenomenon could also have a maternal origin, e.g., by
modifications to the level of resources available to the
Frontiers in Ecology and Evolution | www.frontiersin.org
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding author.
AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct, and intellectual
contribution to the work, and approved it for publication.
FUNDING
This work was supported by the MAVA Foundation, Rotary
Club Les Sables d’Olonne, and by the following grants:
ANR TRANSCAN (ANR-18-CE35-0009), ARC Linkage
(LP170101105), Deakin SEBE_RGS_2019, and a CNRS
International Associated Laboratory Grant. AB was supported by
the National Cancer Institute of the National Institutes of Health
under Award Number U54CA217376. OV was financed by the
János Bolyai Research Scholarship of the Hungarian Academy of
Sciences (HAS) and the New National Excellence Programme
of the Hungarian Ministry of Innovation and Technology. The
funders had no role in study design, data collection and analysis,
decision to publish, or manuscript preparation.
ACKNOWLEDGMENTS
We would like to thank two referees for very constructive
comments on an earlier version of the manuscript.
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May 2022 | Volume 10 | Article 861103