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\DOI{10.5802/crbiol.159}
\datereceived{2024-05-31}
\daterevised{2024-07-15}
\dateaccepted{2024-08-08}
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\title{Oncogenic processes: a neglected parameter in the evolutionary
ecology of animals}

\alttitle{Les processus oncog\'{e}niques : un param\`{e}tre
n\'{e}glig\'{e} dans l'\'{e}cologie \'{e}volutive des animaux}

\author{\firstname{Fr\'{e}d\'{e}ric} \lastname{Thomas}\CDRorcid{0000-0003-2238-1978}\IsCorresp}
\address{Centre de Recherches Ecologiques et Evolutives sur le Cancer
(CREEC/CANECEV) (CREES), MIVEGEC, IRD 224--CNRS
5290--Universit\'{e} de Montpellier, Montpellier, France}
\email[F. Thomas]{frederic.thomas2@ird.fr}

\author{\firstname{Klara} \lastname{Asselin}\CDRorcid{0009-0000-0430-646X}}
\addressSameAs{1}{Centre de Recherches Ecologiques et Evolutives sur le Cancer
(CREEC/CANECEV) (CREES), MIVEGEC, IRD 224--CNRS
5290--Universit\'{e} de Montpellier, Montpellier, France}

\author{\firstname{Nick} \lastname{MacDonald}\CDRorcid{0000-0002-2230-7164}}
\address{School of Life and Environmental Sciences, Deakin University,
Waurn Ponds, Victoria 3216, Australia}

\author{\firstname{Lionel} \lastname{Brazier}\CDRorcid{0000-0003-0575-2968}}
\addressSameAs{1}{Centre de Recherches Ecologiques et Evolutives sur le Cancer
(CREEC/CANECEV) (CREES), MIVEGEC, IRD 224--CNRS
5290--Universit\'{e} de Montpellier, Montpellier, France}

\author{\firstname{Jordan} \lastname{Meliani}\CDRorcid{0009-0008-8517-8727}}
\addressSameAs{1}{Centre de Recherches Ecologiques et Evolutives sur le Cancer
(CREEC/CANECEV) (CREES), MIVEGEC, IRD 224--CNRS
5290--Universit\'{e} de Montpellier, Montpellier, France}

\author{\firstname{Beata} \lastname{Ujvari}\CDRorcid{0000-0003-2391-2988}}
\addressSameAs{2}{School of Life and Environmental Sciences, Deakin
University, Waurn Ponds, Victoria 3216, Australia}

\author{\firstname{Antoine Marie} \lastname{Dujon}\CDRorcid{0000-0002-1579-9156}}
\addressSameAs{1}{Centre de Recherches Ecologiques et Evolutives sur le Cancer
(CREEC/CANECEV) (CREES), MIVEGEC, IRD 224--CNRS
5290--Universit\'{e} de Montpellier, Montpellier, France}
\addressSameAs{2}{School of Life and Environmental Sciences, Deakin
University, Waurn Ponds, Victoria 3216, Australia}

\shortrunauthors

\keywords{\kwd{Adaptation}
\kwd{Cancer}
\kwd{Evolutionary ecology}
\kwd{Ecosystems}}

\altkeywords{\kwd{Adaptation}
\kwd{Cancer}
\kwd{\'{E}cologie \'{e}volutive}
\kwd{Ecosyst\`{e}mes}}

\thanks{EVOSEXCAN ANR project (ANR-23-CE13-0007) and the Hoffmann Family}

\begin{abstract} 
Cancer is a biological process that emerged at the end of the
Precambrian era with the rise of multicellular organisms.
Traditionally, cancer has been viewed primarily as a disease relevant
to human and domesticated animal health, attracting attention mainly
from oncologists. In recent years, however, the community of ecologists
and evolutionary biologists has recognized the pivotal role of
cancer-related issues in the evolutionary paths of various species,
influencing multiple facets of their biology. It has become evident
that overlooking these issues is untenable for a comprehensive
understanding of species evolution and ecosystem functioning. In this
article, we highlight some significant advancements in this field,
also underscoring the pressing need to consider reciprocal interactions
not only between cancer cells and their hosts but also with all
entities comprising the holobiont. This reflection gains particular
relevance as ecosystems face increasing pollution from mutagenic
substances, resulting in a resurgence of cancer cases in wildlife.
\end{abstract}

\begin{altabstract}
Le cancer est un processus biologique qui a \'{e}merg\'{e} \`{a} la fin
de l'\`{e}re pr\'{e}cambrienne avec l'apparition des organismes
multicellulaires. Traditionnellement, le cancer a \'{e}t\'{e}
principalement per\c{c}u comme une maladie touchant la sant\'{e}
humaine et celle des animaux domestiques, attirant principalement
l'attention des oncologues. Cependant, ces derni\`{e}res ann\'{e}es, la
communaut\'{e} des \'{e}cologistes et des biologistes
\'{e}volutionnistes a reconnu le r\^{o}le central des questions
li\'{e}es au cancer dans les trajectoires \'{e}volutives de diverses
esp\`{e}ces, influen\c{c}ant de multiples aspects de leur biologie. Il
est devenu \'{e}vident que n\'{e}gliger ces enjeux est intenable pour
une compr\'{e}hension exhaustive de l'\'{e}volution des esp\`{e}ces et
du fonctionnement des \'{e}cosyst\`{e}mes. Dans cet article, nous
mettons en lumi\`{e}re certaines avanc\'{e}es significatives dans ce
domaine, soulignant \'{e}galement la n\'{e}cessit\'{e} pressante de
consid\'{e}rer les interactions r\'{e}ciproques non seulement entre les
cellules canc\'{e}reuses et leurs h\^{o}tes, mais aussi avec toutes les
entit\'{e}s constituant l'holobionte. Cette r\'{e}flexion prend une
pertinence particuli\`{e}re alors que les \'{e}cosyst\`{e}mes sont
confront\'{e}s \`{a} une pollution croissante par des substances
mutag\`{e}nes, entra\^{i}nant une r\'{e}surgence des cas de cancer dans
la faune sauvage.
\end{altabstract}

\maketitle

\vspace*{1.5pc}

\twocolumngrid

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\xsection{}

It is now widely accepted that multicellular organisms surpass the
concept of autonomous entities, evolving into intricate systems known
as ``holobionts''~\cite{1,2}. These holobionts encompass
not only the host organism but also a consortium of commensal and
mutualistic microorganisms, alongside a diverse array of parasite taxa,
including viruses, bacteria, fungi, protozoans, and metazoans.
Remarkably, parasites themselves possess a microbiome, adding a layer
of complexity to the interactions that take place~\cite{3}. Research
has extensively \mbox{illuminated} the substantial influence of parasites on
the phenotype of their hosts, uncovering interconnected
eco-evolutionary dynamics between animals and symbionts. This
interconnection manifests itself in virtually every facet of an
animal's behavior, influencing the likelihood of exposure to
infection and subsequent alterations in infection 
consequences~\cite{4}. \mbox{Furthermore,} the behaviors of infected hosts can be
affected by the presence of parasites, resulting in well-documented
changes in host phenotype~\cite{5}. Notably, such alterations often
prove advantageous for the transmission and survival of parasites or,
conversely, represent adaptive responses by hosts aimed at eliminating
infections or minimizing associated costs~\cite{6}. Recent studies
have expanded this paradigm by demonstrating that microbes,
particularly those constituting the intestinal microbiota, exhibit
interactions with hosts akin to parasites. Lifestyle factors and social
behaviors of hosts have been shown to influence the microbiota, and
reciprocally, the intestinal microbiota can impact host physiology,
mood, and behavior (e.g.,~\cite{7}). These intricate relationships
underscore a dynamic network shaping the biology and behavior of
multicellular organisms, highlighting the multifaceted interplay
between hosts, parasites, and microbiota.

Beyond microbiota and parasites, multicellular organisms share a
complex evolutionary history with a distinct category of internal
entities: malignant cells~\cite{8}. Originating from normal cells that
undergo a shift in behavior during the host's lifetime, becoming
malignant, these cells proliferate at rates surpassing those of normal
cells. Oncogenesis, which is omnipresent among multicellular species,
occurred for nearly a billion years, dating back to the transition from
unicellular to metazoan life (Appendix~\ref{app1}). The evolution and
diversification of multicellular organisms would have been unattainable
without the establishment of diverse and efficient anticancer defenses
(Appendix~\ref{app2}), which indirectly underscores the importance of
cancerous processes in the evolution of metazoans.

While not always leading to invasive cancers, there is a growing
recognition that oncogenic phenomena, spanning from precancerous
lesions to metastatic cancers, are prevalent in host
populations~\cite{9}. This challenges the conventional perspective that
primarily focuses on relatively well-developed tumors, which are most
often found in post-reproductive individuals. Over the course of an
organism's life, the duration of interactions between a host and its
 oncogenic manifestations can vary from a few months to several years,
or even several decades, with effects on the host that are not fully
documented at all stages. 

In contrast to microbiota and parasites, malignant cells typically do
not spread between host individuals, except for some exceptions where
cancer becomes transmissible, yielding the emergence of a novel
(parasitic) species, which subsequently undergoes its own evolution
(Appendix~\ref{app3}). 

Akin to microbiota and parasites, specific host phenotypic traits can
influence the dynamics of malignant cells, and these cells, in turn,
can instigate phenotypic alterations in the host. Certain host
phenotypic traits may act as underlying causative factors for cancer,
while simultaneously being influenced by the progression of malignancy,
potentially leading to intricate cycles reminiscent of those observed
in specific host-parasite interactions~\cite{10}. Furthermore,
mounting evidence suggests reciprocal interactions between malignant
cells, symbiotic microbes and parasites, indirectly impacting the
interplay between host phenotype and symbionts (Figure~\ref{fig1}). The
potential for triple reciprocal interactions involving malignant cells,
symbionts, and hosts has been historically overlooked, primarily
because evolutionary biologists have tended to disregard or classify as
``noise'' the host phenotypic variations resulting from oncogenic
processes. 

\begin{figure*}
\includegraphics{fig01}
\caption{\label{fig1}Interactions between oncogenic processes, host,
infectious agents and microbiota (adapted from~\cite{10}).}
\vspace*{-2pt}
\end{figure*}


In this article, we delve into several critical dimensions of cancer
biology and its ecological implications. First, we explore the profound
impact of cancerous processes on host phenotype, shedding light on how
subclinical tumor stages can contribute to broader interindividual
variability. Next, we examine the intricate interactions between cancer
and symbiotic organisms, unraveling their implications for cancer
dynamics within ecological contexts. We then pivot to discuss the
evolutionary ecology of host-tumor interactions in polluted ecosystems,
highlighting how environmental factors shape oncogenic phenomena. By
synthesizing these insights, we aim to elucidate the complex interplay
between cancer \mbox{biology,} ecology, and evolutionary processes, offering a
comprehensive perspective on the multifaceted nature of cancer in
natural environments.
\vspace*{-2pt}

\section{Effect of cancerous processes on phenotype}

\vspace*{-1pt}

Most investigations into phenotypic changes in individuals with tumors
have focused on post-diagnosis periods, typically when tumors become
detectable, which may occur years or even decades after the onset of
cancer. There is a need for a more comprehensive exploration of when
phenotypic changes induced by malignant cells occur during the early
stages of tumorigenesis, because it is plausible that the process
itself triggers some alterations in the host phenotype. Given the
parasitic-like interactions between malignant cells and their hosts, it
is first reasonable to assume that these cells may impact the host
phenotype through unintended consequences, such as non-functional
by-products that are adaptive for neither party (see for
instance~\cite{11}). Beyond these unintended effects, there is also an
expectation that malignant cells might contribute to host
manipulation~\cite{12}, especially when tumors are
transmissible~\cite{13}. Changes in the host phenotype may also arise
from adaptive responses by the host aiming to eliminate the malignant
cells (e.g.,~\cite{14}). Cancer defenses designed to counteract
malignant cells (see Appendix~\ref{app2}), similar to general protective
mechanisms, are likely to involve trade-offs with other functions with
consequences at the cell, individual, population, species, and
ecosystem levels (see~\cite{15,16,17} for reviews, Appendix~\ref{app4}).
Hence, even in seemingly cancer-free organisms, the influence of
oncogenic processes on the host phenotype should not be disregarded,
given the potential costs of preventing the progression of microscopic
cancer cell colonies into lethal tumors. In cases where the growth of
cancer is inevitable, individuals may react adaptively to minimize
impacts, such as adjusting life-history decisions to reproduce early
before the detrimental effects of cancer become pronounced (see
Appendices~\ref{app2} and~\ref{app4}). Recent arguments 
(see Appendices~\ref{app2}
and~\ref{app4}) suggest that phenotypic alterations beneficial for
individuals with tumors, maximizing their fitness before death, may
inadvertently support tumor progression (or transmission in the case of
the tumoral hydra), especially if cancer-induced death occurs late in
life when natural selection is weakened.

\section{Interactions with symbiotic organisms and their implications
in cancer dynamics}

The role of infections in the genesis of cancer is well acknowledged,
with an expanding list of pathogens identified as potential
contributors to oncogenesis both in humans and wildlife~\cite{18,19}.
The immune system's central role in surveilling and regulating
malignant cells is crucial, and any disruptions in immune homeostasis,
often triggered by infections, can impact the proliferation of
malignant cells~\cite{20,21}. An underexplored scenario we propose here
is that oncogenic phenomena in wildlife may initiate complex cycles.
Hosts grappling with poor health conditions due to malignancies may
become more \mbox{susceptible} to increased parasite occurrences and infection
intensities, further compromising their resilience and heightening the
likelihood of subsequent infections and cancer progression. Given the
ubiquitous presence of parasites, the coexistence of co-infections, and
the persistent proliferation of malignant cells throughout an
organism's life, there is a pressing need for a deeper understanding of
how parasite communities may either mitigate or exacerbate the
processes of carcinogenesis\cite{20,21,22}. 

In addition to potential interactions between malignancies and
pathogens, there exists a compelling interplay with the microbiota,
gaining recognition for its potential role in
carcinogenesis~\cite{23,24,25}. Altered interactions among the
microbiota, intestinal epithelium, and the host immune system have been
associated with various diseases, including cancer~\cite{26,27}. The
microbiota's pro-tumoral role, linked to inflammation, comes to the
forefront, with disruptions in mucosal/epithelial barriers leading to
the induction of pro-inflammatory cytokines, ultimately fostering tumor
growth~\cite{27,28,29}.

Colon carcinogenesis, as an illustrative example, is profoundly
influenced by the microbiota inhabiting the colon. These microorganisms
play a crucial role in various aspects of colon health, including the
metabolism of substances like retinoic acid, which can impact cancer
development~\cite{30}. Furthermore, the complex interactions between
malignant cells and the microbiota extend to their influence on the
host immune system. Malignant cells and their \mbox{byproducts} can affect the
effectiveness of adaptive immunity, which in turn influences the
diversity and abundance of the microbiota~\cite{31,32}.
Conversely, the microbiota itself plays a significant role in
modulating immune responses against tumors, contributing to
anti-tumoral surveillance mechanisms that help prevent or limit tumor
growth~\cite{33}. This bidirectional relationship underscores the
dynamic interplay between the microbiota, the immune system, and colon
cancer progression.

Microbial products further mold T-cell repertoires and may regulate
anti-tumor responses by priming cross-reactive T cells specific to both
bacterial and tumor antigens. The exploration of host-microbiota
interactions and the determination of specific microbiota's causal
roles in cancer remain vibrant areas of research. While the presence of
bacteria in tumors may hint at associations with certain cancers, it
could also signify local infections within existing malignant tissue,
resembling opportunistic infections within established
tumors~\cite{33}. Beyond bacteria, there is growing evidence supporting
the role of both commensal and pathogenic fungi in influencing various
cancer-related processes. These mechanisms encompass local effects
within the tumor microenvironment and remote influences through the
secretion of bioactive metabolites, modulation of host immunity, and
interactions with adjacent bacterial commensals~\cite{34,35}. However,
it is a recent field of research still in its infancy, and much is
still to be uncovered, especially in wildlife species.

\section{Ecology and evolutionary consequences of oncogenic phenomena}

The presence of oncogenic phenomena in hosts is anticipated to induce
significant changes in key \mbox{ecological} variables, encompassing
competitive abilities, foraging strategies, metabolism, immune
competence, vulnerability to predators, and dispersal
capabilities~\cite{36}. These anticipated effects parallel our
expectations for how microbiota and parasites influence these
ecological processes~\cite{37}. However, the indirect impacts on
ecosystem functioning and the potential evolutionary feedbacks, where
the host's biology is shaped by oncogenic processes, remain poorly
understood at the moment. The consequences of varying susceptibilities
to cancer among species will depend on the ecological status of the
most impacted species, if they are for instance predators, prey, or
keystone species~\cite{38,39,40}. For instance, transmissible cancer in
Tasmanian devils (\textit{Sarcophilus harrisii}) has significantly
reduced the population size of this scavenger species, leading to a
series of cascading effects with major ecological consequences,
including impacts on the abundance of invasive species~\cite{41}. Let's,
however, keep in mind that the dramatic consequences observed at the
ecosystem level with the Tasmanian devil's cancer are undeniably linked to
the fact that this cancer is transmissible, which means it can cause
the same devastation as a other infectious agent. In other words, the
consequences at the ecosystem level with classic, non-transmissible
cancers are certainly less severe. The phenotypic changes induced by
oncogenic processes in hosts also have the potential to alter various
interactions between the affected organisms and other species within
the ecosystem. For example, tumor-bearing hydra exhibit modified
interactions with other species compared to their healthy
counterparts---they capture more prey, are more susceptible
to predation, and experience heavier colonization by commensal
ciliates~\cite{42} (see~also~\cite{43}). Recently,  Tissot et~al.\ 
\cite{Tissotetal} also experimentally demonstrated that tumoral  hydra
act as superspreaders of commensal ciliates, i.e., not only do ciliates
multiply faster on tumoral polyps, but this phenomenon also leads to a
higher colonization rate on other hydra polyps, whether they are of the
same species or not (i.e., spillover). In general, it is known that
cancers often lead to immunosuppression in hosts, and consequently it
is important, from both a health and conservation perspective, to
assess how the resurgence of cancerous pathologies in wild animals may
boost parasitic communities and their \mbox{circulation.}\looseness=-1

In instances where the changes triggered by malignant cells in host
phenotypes occur before the end of the reproductive period, their
influence could extend to immediate and long-term natural selection
pressures on hosts. Consequently, selection becomes shortsighted when the
correspondence between genotype and phenotype is reduced. Analogous to
the effects observed with microbiota and parasites (e.g.,~\cite{44}),
malignant cells may disrupt the linkage between selection acting on
phenotypes and selection operating on genotypes. Consequently, a
plausible outcome of the influence of malignant cells could be a
deceleration of evolutionary changes, particularly as long as
individuals with tumors persist in passing on their genes to successive
generations.


\section{Evolutionary ecology of host tumor interactions in polluted
ecosystems} 

A growing body of research indicates that wildlife is increasingly
susceptible to cancer compared to the past~\cite{45,46,47}. Examples in
emblematic species include St. Lawrence beluga whales
(\textit{Delphinapterus leucas}), green sea turtles (\textit{Chelonia
mydas}), California sea lions (\textit{Zalophus californianus}), and
numerous fish species. The most plausible hypothesis for this abnormal
increase in cancers is attributed to human activity, leading to humans
being labeled as the ``oncogenic species'' for wildlife~\cite{46}. As
for humans, the escalating oncogenic risks produced by anthropic
activities render previously evolved \mbox{anticancer} \mbox{defenses} inadequate
(i.e., evolutionary mismatch, see Appendix~\ref{app4}). These activities
encompass mutagenic pollution of the environment, dietary changes, and
reductions in genetic diversity (intensifying inbreeding issues) of
wildlife species. Exposure to mutagenic sources can influence various
genetic and physiological processes in organisms, requiring a
comprehensive understanding of their collective contribution to the
observed phenotypic changes in each species. In the context of
conservation facing this unprecedented situation, it is crucial to move
beyond more observations and precisely dissect the diversity and impact
of all underlying processes~\cite{48}. To achieve this, it is essential
to comprehend the \mbox{short-,} medium-, and long-term phenomena observed in
organisms and species suddenly exposed to an oncogenic environment
surpassing the one in which their current anticancer defenses evolved
\mbox{(Figure~\ref{fig2}).} These encompass: (i) the expenditure associated
with activating anticancer defenses (and the associated side effects);
(ii) the costs of tumorigenesis itself; (iii) alterations in 
life-history traits; and (iv) the selection for enhanced anticancer
mechanisms. The potential new evolutionary paths that wildlife species
may take will be shaped by the interplay of these effects with
additional selective pressures imposed by the biotic and abiotic
conditions within ecosystems.

\begin{figure*}
{\vspace*{-1pt}}
\includegraphics{fig02}
{\vspace*{-2pt}}
\caption{\label{fig2}Short, medium, and long-term effects of wildlife
exposure to mutagenic ecosystems (adapted from Dujon et~al.~\cite{48}).}
{\vspace*{-2pt}}
\end{figure*}

A first aspect to consider is the expenditure associated with
triggering anticancer defenses. As seen in Appendix~\ref{app2}, cancer
defenses are various, but {irrespective} of the specific defense
mechanisms mobilized, none of them come without associated costs; they
all consume energy that could otherwise be {allocated} to other bodily
functions, giving rise to trade-offs. In an environment undergoing
rapid and abnormal mutagenic changes, the prevalence of oncogenic
processes may significantly rise, prompting the consistent activation
of defenses aimed at thwarting them. The escalated cost associated with
this systematic activation is anticipated to disrupt evolutionary
trade-offs and impose substantial adverse effects on traits such as
survival and/or reproduction (see Appendix~\ref{app4}). It is therefore
possible to consider that these defense mechanisms will be, nowadays, a
sort of Darwinian trap with ultimately negative effects on fitness.
This research field remains, at the moment, poorly explored but appears
highly relevant. Accordingly, some recent studies also suggest that the
cost of activating anticancer defenses is indeed capable of altering
the biology of species (e.g.,~\cite{49}). It is interesting to note
that this hypothesis also leads to the counterintuitive situation in
which we do not observe cancer in a mutagenic environment (due to the
effectiveness of defenses), even though {organisms} will have their
biology significantly altered due to trade-offs. These considerations
are undoubtedly crucial in terms of conservation.

Another important aspect to consider for a better understanding of the
factors influencing phenotypic variations in organisms in mutagenic
environments is, of course, tumorigenesis itself. Organisms will host
various stages of cancerous processes, more or less advanced, and these
processes are not neutral regarding body condition. On the medium term,
selection is expected to adjust life-history traits (see {examples} in
Appendix~\ref{app2}). Additional research is required to investigate the
extent to which adjustments in life history traits favor
population-level and individual responses to cancer risks, and how
easily or rapidly this occurs. If organisms remain exposed to mutagenic
environmental factors over extended periods, natural selection may
favor individuals possessing stronger anticancer defenses, \mbox{conferring} a
selective advantage. However, it is important to consider that the
enhancement of anticancer defenses through selection depends on
specific genetic variations, which may not always occur (given that
mutations happen randomly, limiting the emergence of ``beneficial
mutations''). When such selection is hindered, it is anticipated that
other compensatory adaptations (e.g., menopause as proposed
before~\cite{50}) will be favored, at least temporarily, as
\mbox{alternatives.}\looseness=-1

Thus, several processes can induce phenotypic changes in organisms
experiencing an evolutionary mismatch concerning cancer vulnerability.
Tasmanian devils exhibit resistance, tolerance, or adjustments in
life-history traits in response to the transmissible cancer DFTD. A
critical question is whether adjusting life-history traits is easier to
select for than improved cancer resistance. As oncogenic pressure
intensifies, relying solely on life history trait adjustments may not
suffice for long-term species preservation, necessitating the
development of superior anticancer defenses. For example, in
DFTD-infected Tasmanian devil populations, individuals reproduce
sooner, but further delay reduction is constrained by seasonality. The
transition from life-history trait adjustments to resistance selection
might be occurring, emphasizing the need for continued investigation.
This perspective holds significance not only in \mbox{conservation} biology
but also in ecology and evolutionary biology. Inter-individual
variability, \mbox{traditionally} attributed to genetics or factors like
parasitism, may partly result from subclinical tumor stages. The
consequences of this variability, particularly in early tumorigenesis
stages, and its interaction with anticancer defenses activation remain
poorly understood. Ecological status influences species' persistence,
with potential cascading effects and complex dynamics. The evolving
interplay between host-tumor interactions in mutagenic environments
demands thorough exploration, offering insights into cancer's role in
the evolutionary history of multicellular organisms.

\section{Concluding remarks}

The phenotypic variations between individuals with tumors and their
healthy counterparts largely result from the complex interaction
between a tumor and its host. Exploring these phenomena in the wild is
of crucial importance to deepen our understanding of the pivotal role
played by oncogenic processes in the evolutionary ecology of hosts and
the functioning of ecosystems. Historically, ecologists overlooked the
roles of parasites and the microbiota in host biology and evolution.
However, with the use of more refined methodologies, it becomes evident
that neglecting these aspects is no longer tenable. We advocate for the
recognition of the importance of malignant cells in evolutionary
biology and ecology, emphasizing their equivalent significance with
parasites and the microbiota (see Figure~\ref{fig1}). To embark on this
innovative approach, experimental research should initially leverage
practical animal model systems such as zebrafish, mice or drosophila.
This approach would allow the manipulation of the microbiota,
controlled initiation of cancer (e.g., through genetically modified
organisms), and observation of host phenotypic changes from the onset
of cancer to the conclusion of the life cycle. A multidisciplinary
approach, including mathematical and computational modeling, will play
a central role in developing a holistic perspective. We hope that the
concepts addressed in this paper will consolidate the foundation for a
thorough exploration of the underestimated role of oncogenic processes
in the biology, ecology, and evolution of multicellular hosts. Finally,
we have \mbox{repeatedly} highlighted in this article the impact of cancerous
processes on host phenotypic variation, noting for instance that
subclinical tumor stages could contribute to interindividual
variability \mbox{otherwise} attributed to genetics or parasitism (see above).
We propose to strengthen studies considering cancerous processes as a
potential outcome of embryonic development, thus suggesting an
integration of cancer into the developmental mechanisms that influence
the genotype-phenotype map. This approach could enrich the field by
integrating concepts from evo-devo to better understand these complex\break
dynamics~\cite{51,52,53}.

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.


\section*{Funding}

This work was supported by the EVOSEXCAN ANR project (ANR-23-CE13-0007)
and the Hoffmann \mbox{Family.}


\CDRGrant[ANR]{ANR-23-CE13-0007}

\back{}

\appendix{}

\gdef\appendixlabel{Appendix A}

\section{Cancer, an evolutionary phenomenon that emerged with
the advent of multicellular organisms}\label{app1}

Where does cancer originate? The biological process that leads to this
disease is found in all vertebrate classes, including emblematic
extinct species like the Jurassic dinosaurs~\cite{10,55,56}.
Cancer is also observed in invertebrates such as insects, mollusks, and
cnidarians, like hydras~\cite{57,58}. In actuality, the inception
of cancer dates back approximately one billion years, coinciding with
the emergence of multicellular organisms in the late Precambrian
era~\cite{59} (the oldest known cancer fossils date back 240~million
years in turtles~\cite{60}, and 1.7~million years in
humans~\cite{61}). During this period, life on Earth evolved from
unicellular organisms to more intricate entities known as metazoans,
consisting of thousands, or even billions, of genetically identical
cells working collaboratively. To achieve this, these cells activate
various segments of their genome to specialize and cooperate through
task allocation~\cite{62}. Once this effective cooperative
functioning logic was established, natural selection favored the most
successful cooperative entities---those capable of maximizing
their reproductive success. This involved excelling in resource
acquisition, avoiding predators and parasites, attracting sexual
partners, etc. However, paramount was the need to maintain the
organism's functionality. To achieve this, natural selection during the
evolution of multicellular organisms favored adaptations that
strengthened cohesion and communication between cells to harmonize
their collective functioning. Simultaneously, other adaptations aimed
to prevent, control, or eradicate cells that did not contribute to this
collective effort, thereby restoring unicellular functioning. These
adaptations, selected over millions of years, have significantly
contributed to the remarkable diversification of multicellular
organisms observed today.

The benefit of this collective operation lies in its formidable
efficiency compared to unicellularity. However, like all collective
systems, it remains vulnerable to cheaters. Cheating occurs when
someone gains the benefits of a cooperative system without fulfilling
their necessary contribution to its proper functioning. Thus, one of
the primary challenges in the evolution towards functional
multicellularity has been constraining some of the constitutive cells
to give up their own ability to reproduce. This represents a
significant sacrifice in Darwinian terms, as natural selection
typically favors maximizing reproduction. Nonetheless, the logic holds
because somatic cells, which are non-reproductive, still indirectly
promote the transmission of their genes through the reproductive sex
cells, with which they share the same genome.

Occasionally, following mutations, certain somatic cells, despite their
non-reproductive nature, attempt reproduction nonetheless. If the
resulting conflict of interest is not resolved, it can lead to tumor
formation and eventually cancer. As this challenge has persisted since
the emergence of multicellularity, selection has favored the evolution
of anticancer adaptations capable of effectively suppressing these
cellular rebellions from that early period onwards~\cite{63}.
Nevertheless, cancer cells represent living entities subject to an
evolutionary process guided by natural selection. Consequently, they
possess the ability to dynamically acquire adaptations in real-time,
enabling them to evade anticancer defenses. This dynamic unfolds
precisely during the progression of cancer. Ironically, it is the same
natural selection process that, on one hand, fosters the development of
defenses against cancer and, on the other hand, propels the disease to
advance into an invasive state. Natural selection favors entities that
are most effective at reproduction, irrespective of whether they confer
benefits or harm. The shift from unicellularity to multicellularity
throughout the history of life occurred not as a singular event but
rather took place around a dozen times since the Precambrian era. The
advantages associated with multicellularity played a pivotal role in
driving this transition. However, in each instance, the social dilemma
mentioned earlier emerged, contributing to the ubiquity of cancer as a
disease within all multicellular groups~\cite{56}. 

Although cancer is an ancient ailment, it presents a unique narrative
with each occurrence. Strikingly, in the majority of instances, cancer
is not communicable (although there are exceptions, see
Appendix~\ref{app3}). As a result, the entire spectrum of genetic,
epigenetic, and cytogenetic diversity established during tumorigenesis
vanishes with the demise of the host, be it due to cancer or other
causes. Consequently, cancer is compelled to innovate anew on each
occasion~\cite{64}. It is noteworthy, given these circumstances, that
with each occurrence, there is a transition from a cell detaching from
the collective system to an intricate cooperative system---an
ecosystem within the larger ecosystem (the solid tumor). This pattern
exhibits profound resemblances between organs, individuals, and even
species. Evolutionarily, potential explanations for this phenomenon
include evolutionary convergences (where only cancer cells capable of
organizing in this manner can elude anticancer defenses)~\cite{65}, or
the reactivation of ancestral genetic programs dating back to the
Precambrian era (the atavistic hypothesis of cancer)~\cite{66,67}.
Recently, Thomas et~al.\ \cite{Thomasetal} argued that it also represents a
compelling example of selection for function
(\textit{sensu}~\cite{68}): Natural selection among individual cancer 
cells and cell groups within the tumor, which is originally the engine
of tumor initiation, later serves as a tool to generate various
configurations suitable for various changing and challenging
environments, which is the key to selection for functional optimization
and tumor\break progression.

\gdef\appendixlabel{Appendix B}

\section{Evolution of anticancer defenses among animals} 
\label{app2}

Throughout metazoan evolution, the process of selection has endorsed
the development of a repertoire of mechanisms designed to thwart the
emergence of antisocial cells or identify and repress them~\cite{69}.
These mechanisms function across various levels, encompassing genomes,
cells, tissues, and the entire organism. Multicellular organisms have
faced the selective pressures of natural evolution since their
inception to combat cancer cells. In contrast, cancer cells have a
relatively brief evolutionary history, with a lifespan typically
limited to a few years. Consequently, host organisms have developed
highly effective mechanisms to counteract cancer cells, given their
longstanding adaptation to confront a recurring adversary with each new
generation~\cite{10}. As a result, multicellular organisms, for the
most part, experience invasive lethal cancers infrequently,
particularly during their reproductive phase. However,
post-reproductive stages witness a higher incidence of cancers, as
natural selection no longer upholds the efficiency of anticancer
defenses as robustly~\cite{71}. The logical extension of this reasoning
is that elevating cancer risks, such as through exposure to an
\mbox{oncogenic} environment (see after), leads to a situation where the
anticancer defenses established through evolution are no longer
optimally aligned with the increased risk~\cite{72,73}. Invasive
cancers are more prevalent than anticipated, exemplified by occurrences
in domesticated canids and humans, who have undergone rapid and recent
changes compared to their close ancestors~\cite{74}.

Within the established framework of ecology and evolution, an
increasing number of researchers have recently directed their focus
toward exploring anticancer defense mechanisms within the animal
kingdom. It is noteworthy that, despite the high prevalence of
oncogenic processes in multicellular organisms, there are significant
variations between species. This suggests, albeit indirectly, that
certain species hold unique ``anticancer secrets'', enabling them to
more effectively prevent, eradicate, or tolerate
tumors---reasons for which are still under \mbox{investigation.}

\subsection{Peto's paradox}

Research into cancer resistance in the animal kingdom centers on the
concept known as ``Peto's Paradox''. The underlying rationale is quite
simple: if the initiation of cancer is primarily dependent on
malfunctioning cells, then, logically, a large organism composed of
numerous cells (such as a blue whale, \textit{Balae{}noptera
musculus}, with seven million times more cells than a house mouse,
\textit{Mus musculus domesticus}), and boasting a lengthy lifespan
(whales can live close to a hundred years, while domestic mice have a
lifespan of three to four years), should be more susceptible to cancer.
Each cell division, after all, comes with a risk of mutations leading
to a malignant lineage. Within the same species, this prediction is
often borne out: larger individuals generally exhibit a higher
vulnerability to cancer than their smaller counterparts. Research in
humans and dogs has shown that cancer risks are frequently positively
linked with size~\cite{75}. However, this correlation appears to
diminish when examining different species. Studies reveal no clear
connection between cancer occurrence, body size, and lifespan. Hence,
despite their imposing stature, whales and elephants do not demonstrate
an elevated prevalence of tumors, suggesting an implicit resilience to
cancer~\cite{76}. This paradox is once again elucidated through the
lens of the evolutionary process. Large-sized and long-lived species
have managed to endure and persist to the present by evolving robust
cancer defense mechanisms through natural selection. To envision a
scenario where whales, with a thousand times more cells than humans,
experience a thousand times more cases of cancer suggests that they
likely would not have survived. 

To date, the most extensive examination of Peto's paradox has been
undertaken by Vincze et~al.~\cite{77}. This study focused on captive
wildlife in zoos, specifically looking at 191 mammal species where
health data, including cancer information, had been systematically
gathered (utilizing the Species360 database). Adjusting for various
potentially confounding factors related to zoo conditions, the primary
insights derived from this research are as follows: (1) Cancer-related
mortality risk exhibits significant variation among species, ranging
from 0\% to 57.4\%, as observed in the Kowari, a small carnivorous
marsupial native to Australia; (2) The risk of cancer-related mortality
surpasses 10\% in 41 species, emphasizing that cancer is not confined
to humans and their domesticated animals: it can affect a diverse array
of species provided they live long enough, a condition often met in
zoos; (3) A notable phylogenetic pattern is observed: carnivores tend to
have a higher incidence of cancers compared to primates or
artiodactyls, even when considering that the latter include large-sized
species; (4) Addressing Peto's paradox, the study affirms the lack of a
straightforward correlation between size, longevity, and\break cancer risks.

More recently, Dujon et~al.~\cite{78} have proposed the idea that the
principles of Peto's paradox might extend beyond size and longevity to
encompass other traits. If a particular trait is expected to predispose
to cancer but does not, there is a likelihood that natural selection
has played a role in this divergence from the predicted outcome. An
illustrative example is found in the various types of placentation
among mammals, differing in invasiveness. While one might anticipate
species with highly invasive placentation (hemochorial placenta) to be
more susceptible to metastatic cancers, analysis of the same dataset on
captive wildlife reveals this expectation does not hold true. In
essence, species retaining invasive placentation have concurrently
developed mechanisms that mitigate the risks of metastatic cancers.

\subsection{What mechanisms are at play in preventing cancer?}

In recent years, diverse studies have explored various species for
their resistance to cancer, including naked mole-rats, elephants,
whales, Placozoans, Xenarthrans (sloths, armadillos, and anteaters),
and bats. The primary investigations into naked mole-rats were led by
the team of Vera Gorbunova and Andrei Seluanov~\cite{79,80,81}. The
naked mole-rats are widely recognized for their remarkable resistance
to cancer, making them a focal point in oncology research. Several
biological traits in these animals may contribute to their ability to
prevent tumor development. Notably, fibroblasts in naked mole-rats have
demonstrated the presence of two independent mechanisms that inhibit
cell contact. These mechanisms involve specific regulatory pathways
such as p53, pRb, p16, and p27, which could play a pivotal role in
preventing cancer. The same authors also show that in hyperplastic
precancerous cells, the loss of methylation induces the transcription
of endogenous retroviruses and cell death through the interferon
pathway~\cite{82}. Additionally, naked mole-rats exhibit adaptations in
oxidative metabolism, favoring glucose utilization over oxidative
phosphorylation. This metabolic preference potentially reduces
oxidative stress, limits DNA damage, and contributes to their
resistance to cancer.

The extended lifespan of naked mole-rats (up to 30~years) compared to
similar-sized rodents is noteworthy, suggesting potential connections
to more efficient DNA repair mechanisms or heightened resistance to
cellular aging. Researchers have also explored the unique viscosity of
cell cultures in naked mole-rats, attributed to a dense hyaluronic acid
produced by the cells themselves and expelled into the extracellular
matrix. This characteristic prevents cells from clustering and forming
tumors. To validate whether this specific hyaluronic acid is indeed
responsible for cancer resistance in naked mole-rats, researchers
conducted experiments to block its production in 80~individuals. The
results indicated a \mbox{tendency} for cells to cluster, raising the
possibility of potential tumor formation (see however~\cite{83}). As
suggested by the authors, it remains possible that the primary driver
behind the selection for producing a distinctive hyaluronic acid might
not be primarily for cancer protection but rather as an adaptation to
the subterranean environment. The gradual development of remarkably
flexible integument, serving to shield their exposed skin from injuries
while navigating narrow tunnels dug with their teeth, could be the main
purpose. In this scenario, protection against cancers might emerge as a
beneficial side effect of another adaptation.

Several other mole-rat species, such as the Golan Heights blind
mole-rat (\textit{Spalax golani}) and the blind mole-rat from the
Judean Mountains (\textit{Spalax judaei}), display strong
resistance to cancer. Initial expectations of finding similar defense
mechanisms as observed in the naked mole-rat were not met. Researchers
isolated cells from these rodents, cultured them, inducing
multiplication beyond what naturally occurs in the animals' organs.
During the first seven to twenty phases of multiplication, everything
proceeded normally. However, beyond the twentieth multiplication, the
cells started to undergo rapid mortality~\cite{84}. Analysis of the
dying cells revealed the initiation of interferon beta
(IFN-${\upbeta}$) release, triggering massive death of necrotic cells
within three days. Essentially, once the cells recognized they had
surpassed a critical multiplication threshold, apoptosis was activated.
Notably, different proximal mechanisms have been selected in all cases
to confer resistance to cancer processes. This underscores an
evolutionary convergence where similar ecological contexts lead to
analogous adaptations, even if not rooted in the same precursors.

The ability of elephants to resist cancer has been linked to specific
genetic characteristics, particularly the amplification of the TP53
gene copies. The TP53 gene plays a crucial role in suppressing tumors
and repairing damaged DNA. African and Asian elephants have been
observed to possess multiple copies of this gene (around twenty), a
notable contrast to humans, who have only one copy. When DNA damage
occurs, the TP53 gene becomes activated, regulating the cellular
response and potentially inducing programmed cell death (apoptosis) in
damaged cells, thereby preventing tumor development. However, the
precise functionality of these additional copies remains a topic of
ongoing debate~\cite{85}. Another process acting in elephants is the
reactivation of a ``zombie gene'' known as LIF6~\cite{86}. While the
LIF gene, a leukemia inhibitory factor, is typically present in a
single copy in mammalian genomes, elephants have ten copies. However,
aside from LIF6, these extra copies are non-functional, having
accumulated mutations over time, rendering them incapable of producing
their protein correctly---referred to as ``pseudogenes''. In
contrast, the LIF6 gene has regained functionality, actively
contributing to the destruction of cancer cells. Importantly, the
reawakened activity of this gene remains under the control of the TP53
gene. Thus, TP53 not only identifies cells with damaged DNA but also
triggers other genes that reinforce anticancer defenses.

In Xenarthrans, a group that includes sloths, armadillos, and
anteaters, various lineages have independently developed large body
sizes, long lifespans, and an inherently reduced susceptibility to
cancer. Recent investigations~\cite{87} demonstrate that this
diminished vulnerability aligns with surges in duplications of tumor
suppressor genes within the fundamental lineages of Xenarthrans and
pilosids (pilosids are a subgroup of Xenarthrans, and they include
anteaters and sloths, while Xenarthrans also encompass cingulata, such
as armadillos). Sloths exhibit an exceptionally sluggish cell
proliferation rate, while other Xenarthrans trigger apoptosis even at
minimal doses of DNA-damaging agents. Consequently, the occurrence of
cancer is remarkably low in Xenarthrans, with nearly no instances
reported in armadillos. These findings imply that the amplification of
tumor suppressor genes has played a pivotal role in the evolution of
significantly large body sizes and a reduced risk of cancer in
Xenarthrans, establishing them as remarkable cancer-resistant mammals. 
\looseness=-1

In 2021, a study~\cite{82} exposed the Placozoan \textit{Trichoplax
adhaerens} to elevated doses of X-rays to explore how this species
managed the presence of mutated cells. \textit{T. adhaerens} displayed
an impressive capacity to endure high levels of radiation, showcasing
resilience in the face of DNA damage~\cite{82}. Upon exposure to
X-rays, these organisms responded by expelling clusters of cells,
ultimately leading to their demise. Essentially, they expelled
potentially hazardous cells from their organism. This exposure to
radiation also triggered heightened activity in genes associated with
DNA repair and the apoptosis process. 

Studies on bats suggest that their resistance to cancer can be
attributed to at least two distinct factors: a reduction in the
signaling of growth hormone and insulin-like growth~factor-1 (IGF-1),
coupled with alterations in microRNA patterns~\cite{81}. Both growth
hormone and IGF-1 are pivotal molecules in cell growth and metabolic
regulation, with heightened levels typically linked to tumor growth and
cancer development. The diminished signaling of these hormones in bats
may thus play a role in impeding tumor growth. MicroRNAs, small RNA
molecules governing gene expression, undergo specific changes in bats
that likely contribute to their cancer resistance. In the genomic
analysis of the Mesoamerican mustached bat (\textit{Pteronotus
mesoamericanus}), researchers identified positive selection in 33~tumor
suppressor genes and 6~DNA repair genes, potentially influencing their
lower cancer susceptibility and increased lifespan~\cite{88}.

Cetaceans, encompassing various species renowned for their size, such
as the blue whale (\textit{Balae{}noptera musculus}) with an
average length of 25~to 27~meters and weighing 130~tons, as well as
their impressive longevity, exemplified by the bowhead whale
(\textit{Balaena mysticetus}) that can live over 200~years, have
been the focus of extensive research. These studies have not
consistently uncovered the presence of additional copies of tumor
suppressor genes, a characteristic that seems to be lacking in certain
species like the minke whale (\textit{Balaenoptera
acutorostrata})~\cite{89}, the bowhead whale
(\textit{Balaena mysticetus})~\cite{32}, the sperm whale
(\textit{Physeter macrocephalus})~\cite{90}, or the
humpback whale (\textit{Megaptera novaeangliae})~\cite{91}.
According to a study conducted by Sun et~al.~\cite{92}
encompassing 22~cetacean species, genes exhibiting an evolution
correlated with body size are primarily associated with immune
surveillance, tumor suppression, and the development of hypertumors
(discussed later). Concerning the immune system, the authors propose
that the primary focus of selection may not necessarily be on defending
against cancer processes but rather on the necessity to combat
parasitic infections. In larger species, which inhabit a broader range
of habitats encompassing both freshwater and saltwater environments,
parasitic infections tend to be more prevalent. These infections can
manifest at an early age and pose a short-term threat, in contrast to
cancers, which are seldom immediately life-threatening. Consequently,
the evolutionary imperative might be centered around managing parasitic
challenges, and the enhanced resistance to cancer could be an
incidental outcome of other adaptive mechanisms. The concept of
hypertumors is relatively obscure and original. Initially introduced in
2007~\cite{93}, this hypothesis is built on the notion that a
strategy to combat tumors involves allowing other tumors to establish
themselves within, leveraging the familiar principle that ``the enemy
of my enemy is my friend''. In contrast to the Peto's paradox logic,
which proposes that cancer resistance rises with size and/or longevity,
the hypertumor hypothesis suggests that beyond a certain size/longevity
threshold, it could be evolutionarily advantageous to deactivate
specific anticancer defenses. Consequently, cancer cells, as
exploiters, might exploit the cancer system they originate from,
ultimately weakening the original tumor.

Finally, with the increasing availability of species genomes in
scientific literature, comparative genomics is emerging as a valuable
tool for exploring the evolution of anticancer defenses across the
animal kingdom. This includes investigating instances of evolutionary
convergence, as demonstrated in studies such
as~\cite{94,95,96}. For instance, a comprehensive
analysis~\cite{95}, covering 193~vertebrates, spanning mammals,
birds, fishes, and reptiles, indicated that genes exhibiting greater
conservation in species with higher cancer rates were primarily
associated with metabolic functions. Conversely, genes showing higher
conservation in species with lower cancer rates were linked to cell
cycle regulation, DNA repair, and immune response. These comparative
approaches further support the notion that animal species with larger
body masses have evolved specific cellular mechanisms to counteract
mutation accumulation and maintain genetic stability. This adaptive
trait may elucidate the absence of an increased incidence of cancer
despite prolonged exposure to potential mutagenic factors. In summary,
it is imperative to acknowledge the varied susceptibility of species to
cancer. Contrary to expectations, larger and/or longer-lived species do
not display higher susceptibility to cancers, and diverse solutions to
Peto's paradox have been identified (also refer to
reviews:~\cite{97,98}). This observation aligns with the fact that
large sizes have independently evolved multiple times in the history of
multicellular organisms.

\subsection{Considering all ecological constraints}

To gain a comprehensive understanding of the evolution of anticancer
defenses in the animal \mbox{kingdom,} it is crucial to consider all the
ecological constraints that animals face in real ecosystems. Anticancer
defenses, by their nature, can only be optimal rather than maximal in
the living world. This is because they are not the sole priority for
organisms, and there are inherent compromises and constraints. For
instance, in ecologically unstable environments, positive selection
might have occurred for an increased germline mutation rate, promoting
greater genetic diversity as part of a ``bet-hedging'' strategy, even
though it could subsequently elevate cancer risks~\cite{99}.
Furthermore, natural selection predominantly favors reproduction over
survival. This means that strategies leading to improved reproduction
will be favored, even if they entail an increased risk of cancer later
in life~\cite{16}. In Tasmanian devils (\textit{Sarcophilus
harrisii}), engaging in fights and bites to access mates exposes
individuals to the risk of contracting the transmissible and lethal
cancer DFTD. However, a strategy of avoiding aggressive interactions
with other individuals is not evolutionarily viable. Even if
individuals adopting such a strategy were to live longer by avoiding
DFTD, they would not pass on their genes to the next generation. From a
natural selection standpoint, it is more advantageous to compete for
reproduction, even if it comes with the risk of earlier death from
cancer. Another consideration is that anticancer adaptations that are
``too'' effective might result in significant collateral damage, such
as autoimmune diseases. This evolutionarily unsustainable constraint
has likely been a significant obstacle to the potential selection of
more potent anticancer adaptations. Additionally, certain adaptations
(e.g., for rapid early-life growth, increased aggression) may rely on
genetic variants associated with antagonistic pleiotropy, meaning they
are retained by natural selection due to the advantages they provide
early in life, even if they promote cancer development later
on~\cite{100}. Natural selection has favored behavioral strategies in
the animal kingdom to prevent or mitigate the impact of cancer. For
instance, birds like tits and flycatchers around Chernobyl can choose
nests in less irradiated areas~\cite{101}. In the case of drosophila
with cancer, they tend to prefer social environments that slow down the
\mbox{disease's} \mbox{progression~\cite{102}.} Additionally, research in various
species, including fruit flies~\cite{103}, hydra~\cite{104} and
Tasmanian devils~\cite{105}, indicates that animals with cancer may
have a shorter lifespan, but many prioritize immediate reproductive
efforts before succumbing to the illness. This adaptation, observed in
host-parasite interactions, seems to also play a role in interactions
with tumors, allowing for the maximization of offspring despite the
presence of the disease.

\gdef\appendixlabel{Appendix C}

\section{Evolution of transmissible\newline cancers} \label{app3}

{At present, there are fourteen documented instances of transmissible
cancers in the wild. Two impact the Tasmanian devil~\cite{106}
(Figure~\ref{fig3}), one affects the Canidae~\cite{107}, and eleven are
identified in bivalves, some of which possess the ability to cross
species barriers~\cite{108,109}. The transmissibility of these
cancer cells aligns their evolutionary dynamics more closely with
emerging pathogens, fostering long-term co-evolution with their hosts.
For example, after approximately forty years since its emergence, the
transmissible cancer line associated with Devil Facial Tumor Disease
(DFTD) in Tasmanian devils appears to transform into an obligatory
parasite, engaging in genuine co-evolution with its host. Additionally,
transmissible tumors have been mentioned in the freshwater cnidarian
\textit{Hydra oligactis} (Figure~\ref{fig4}). Remarkably, these tumors
and their distinct microbiome can be vertically transmitted during
asexual reproduction (hydras generate buds that grow into distinct
polyps). A surprising aspect of the external phenotype in certain
tumorous hydras is the increased number of tentacles, which can
escalate from 6--8~to around 20. A recent study~\cite{13}, employing a
tumor grafting protocol, demonstrated that the manipulation of the host
phenotype is attributed to the tumor cells. The increased number of
tentacles enables the hydra to capture more prey, facilitating
increased budding and promoting tumor transmission. While tumor cells
in general are known to manipulate their immediate environment,
inducing processes like neoangiogenesis to nourish the tumor, this
represents the first example of a tumor capable of influencing the
external phenotype of its host, akin to how parasites manipulate
behavior. This research supports the notion that transmissible cancers,
due to their lifestyle remarkably similar to parasites, evolve under
similar constraints as parasites \textit{sensu stricto}, developing
comparable adaptations through selection.

\begin{figure}
\includegraphics{fig03}
\vspace*{-3pt}
\caption{\label{fig3}\fontsize{9.5}{12}\selectfont 
Tasmanian Devil (\textit{Sarcophilus harrisii}), (A)
healthy individual, (B) individual with a small tumor DFTD1 and (C)
individual with a large tumor DFTD1 (Photo Credit, Fr\'{e}d\'{e}ric
Thomas).}
\vspace*{-3pt}
\end{figure}

\begin{figure*}
\vspace*{-3pt}
\includegraphics{fig04}
\vspace*{-3pt}
\caption{\label{fig4}\textit{Hydra oligactis}, healthy and
tumoral polyps. In addition to the body being deformed due to tumors,
we can notice the presence of additional tentacles, resulting from a
manipulation of the host by tumoral cells~\cite{13}.}
\vspace*{-3pt}
\end{figure*}

\begin{figure*}
\includegraphics{fig05}
\caption{\label{fig5}The emergence and spread of transmissible cancers
hinge on a ``Perfect Storm'', a precise set of conditions. Human
activities have the potential to impact both of these crucial
components (adapted from~\cite{111}).}
\end{figure*}

While the exact prevalence of transmissible cancers remains unknown,
these unusual malignancies are likely to be rare in the wild. The
underlying reasons for this rarity are only partly comprehended, and
the ``Perfect Storm hypothesis'' proposes that transmissible cancers
are infrequent due to the specific alignment of tumor and host traits
necessary for their occurrence~\cite{110}. This explanation appears
plausible, as transmissible cancers, akin to emerging pathogens, would
require specific biotic and abiotic conditions not only for their
emergence but also for their propagation to detectable
levels~\cite{111} (Figure~\ref{fig5}).\break Given the rarity of these
conditions, transmissible cancers would infrequently spread and, most
of the time, dissipate despite sporadic appearances. Therefore, further
research is essential to identify the key factors that may either
facilitate or impede the emergence and evolution of transmissible
cancers. This inquiry gains significance as human activities
progressively encroach upon wild habitats, causing alterations in
ecosystems and their dynamics, potentially influencing the conditions
conducive to the emergence and dissemination of transmissible cell
lines, e.g.,~\cite{112}.\looseness=-1
}

\gdef\appendixlabel{Appendix D}

\vspace*{-2pt}
\section{Ecological and evolutionary\newline consequences of anticancer\newline adaptations} 
\label{app4}
\vspace*{-2pt}

{Oncogenic processes are present across various branches of
multicellular life. This phenomenon promotes the evolution of
adaptations aimed at preventing or suppressing malignant progression
and mitigating its impact on fitness. The significance of cancer cells
in animal ecology has been largely overlooked by ecologists until
recently, possibly due to a lack of consideration for the potential
ecological and evolutionary repercussions of anticancer adaptations.
However, evolution of anticancer adaptations has substantially
constrained several facets of the evolutionary ecology of multicellular
organisms at the cellular, individual, population, species, and
ecosystem levels~\cite{15}. 

\vspace*{-2pt}
\subsection{Cell level}
\vspace*{-2pt}

Cancer defenses, while crucial for preventing tumors, can have
unintended consequences and trade-offs that influence aging,
regenerative capacity, and the prevalence of inherited mutations. These
defenses are a double-edged sword, offering protection against cancer
but at the same time, potentially accelerating the aging process. For
instance, the P53 protein acts as a major cancer defense by interfering
with normal cell activities, including cell cycle control, DNA repair,
and the induction of cell death. This protein is a vital tumor
suppressor, ensuring that cells with damaged DNA do not proliferate
uncontrollably. However, its activation may have antagonistic
pleiotropic effects, as it can impede the proliferation of normal
cells, contributing to aging-related issues~\cite{62,113}. When P53 is
activated, it can lead to cellular senescence, a state in which cells
permanently stop dividing. While this process prevents the formation
and growth of tumors, it also means that the body's ability to
replenish cells is reduced. Over time, the accumulation of senescent
cells can contribute to tissue degeneration and the functional decline
associated with aging. Moreover, senescent cells secrete inflammatory
cytokines, growth factors, and proteases, collectively known as the
senescence-associated secretory phenotype, which can disrupt the tissue
microenvironment and promote age-related pathologies. In addition to
promoting senescence, the activation of P53 can also induce apoptosis,
or programmed cell death, in cells with severe DNA damage. While
apoptosis is a critical mechanism for eliminating potentially cancerous
cells, excessive apoptosis can lead to a decrease in regenerative
capacity. Tissues with a high turnover rate, such as the skin, blood,
and gut, are particularly vulnerable to the loss of regenerative cells,
resulting in impaired tissue repair and maintenance as we age.
Furthermore, the trade-offs in cancer defenses can influence the
prevalence of inherited mutations. High fidelity in DNA repair
mechanisms reduces the risk of mutations that could lead to cancer.
However, stringent DNA repair processes can also limit genetic
diversity and adaptability, potentially impacting {evolutionary} fitness.
The intricate balance between preventing cancer and allowing for
cellular regeneration and repair underscores the complexity of the
biological systems governing aging and disease. Thus, while mechanisms
like the P53 pathway are indispensable for cancer prevention, they
illustrate the inherent biological trade-offs that impact aging and
senescence. Understanding these relationships is crucial for developing
interventions that can mitigate the adverse effects of aging while
maintaining effective cancer defenses~\cite{114,115}. Additionally,
cancer defenses that prevent neoplasm formation due to somatic
mutations may paradoxically promote cancer. These defenses limit the
detrimental effects of somatic mutations but also protect inherited
mutations from purging by purifying selection, contributing to the
higher frequency of oncogenic congenital mutations in
\mbox{populations~\cite{114}.}\looseness=-1

{\vspace*{-2pt}}

\subsection{Individual level}

{\vspace*{-2pt}}

Individuals exhibit variations in their susceptibility to malignant
cells and their ability to manage them, \mbox{influenced} by genetic and
environmental factors~\cite{116}. This diversity extends to physiology,
behavior, and life-history traits within species, affecting cancer risk
and responses. For instance, individuals with high activity rates and
metabolic rates tend to have lower cancer risk~\cite{117}. At the
intraspecific level, different combinations of factors influence
inter-individual performances, impacting traits like 
reproductive investment~\cite{16} and vulnerability to
predators~\cite{36}.

The evolution of prophylactic behaviors against cancer, such as habitat
selection, has been explored, highlighting potential
trade-offs~\cite{37}. Curative behaviors are considered more likely
than preventive ones due to the association of malignancies with
detectable internal cues. The effects of subclinical cancers on fitness
in wild animals remain unknown, but potential trade-offs are expected,
prioritizing cancer concerns over activities like reproduction.
Self-medication in response to cancer is uncertain, and strategies to
conserve energy or alter behaviors may emerge. Empirical studies,
though limited, demonstrate altered reproductive schedules and social
behaviors in individuals with early-stage tumors.

The influence of oncogenic processes on individual behavior in wildlife
is underexplored, partly due to challenges in detecting cancer. Sexual
selection is suggested as a promising avenue for exploration,
considering potential trade-offs between energy allocation for cancer
suppression and early-life reproductive activities (see for
instance~\cite{118,119}). Sexual selection may also favor
oncogene alleles in certain cases, as observed in the fish genus
\textit{Xiphophorus}, where the oncogenic \textit{Xmrk} allele persists
in natural populations, suggesting benefits early in life that outweigh
later costs through antagonistic pleiotropy~\cite{100}.

\subsection{Population level}

Beyond individual-level plastic adjustments, the necessity for cancer
defenses might shape the life-history of populations and species over
the long term. Coevolving with oncogenic manifestations, individuals in
certain populations may evolve a constant tumor-suppressive strategy,
even in the absence of malignant cells.

One potential example of anticancer adaptations altering life-history
traits involves Tasmanian \mbox{devils} heavily infected with DFTD, displaying
a shift towards single breeding with individuals exhibiting precocious
sexual maturity~\cite{105}. Exploring relationships between tumor
development in wildlife and environmental contaminants, such as those
from aluminum smelting facilities or organochlorine contaminants,
reveals the intricate interplay of ecological factors, life-history
characteristics, cancer defense mechanisms, and pollutant
effects~\cite{120}. Local adaptations to cope with pollution are
evident in various species, with fitness costs associated with these
adaptations sometimes becoming apparent when individuals from polluted
habitats are placed in non-polluted conditions. One of the most
prominent illustrations of the swift and significant increase in the
risk of mutagenic and potentially carcinogenic effects from modern
human activities is the substantial release of radioactive isotopes
into the air, soil, and water following the nuclear accidents in
Chernobyl, Ukraine, in 1986, and Fukushima, Japan, in 2011~\cite{121}.
These incidents are notable not only for their profound impact but also
for representing only the visible aspect of a broader issue. Human
activities contribute to numerous mutagenic effects that may not be as
conspicuous but should not be overlooked, given the implications of
chronic exposure to low doses. Moreover, consensus is lacking on the
long-term effects of chronic radiation exposure on wildlife in the
Chernobyl Exclusion Zone and Fukushima area (see~\cite{122,123}),
highlighting the imperative for further research in these areas.

The theoretical concept of ``evolved dependence'' arises, suggesting
that adapted individuals achieve higher fitness in the presence of
oncogenic processes~\cite{120}. For instance, in Tasmanian devils with
precocious sexual maturity, it might be expected that their fitness is
lower than other individuals in the absence of the disease. This
phenomenon, despite being poorly considered by ecologists, indicates
local adaptations to cancer risk, which could be selected for in just a
few generations in various organisms.

\begin{figure*}
{\vspace*{-2pt}}
\includegraphics{fig06}
{\vspace*{-2pt}}
\caption{\label{fig6}Overview of the impact of cancer
defense costs across various levels in the living world, spanning from
cellular levels to individuals, populations, species, and ecosystems
(adapted from~\cite{15}).}
{\vspace*{-2pt}}
\end{figure*}

\subsection{Species level}

At the species level, it is commonly believed that the need to suppress
somatic evolution should increase with larger body sizes and longer
lifespans. However, as explained in Appendix~\ref{app2}, ``Peto's Paradox''
challenges this assumption, indicating no correlation \mbox{between} body
size, longevity, and cancer rates across species. Recent studies reveal
genomic mechanisms in large-bodied and long-lived species, such as
elephants and whales, that enhance cancer suppression (see
Appendix~\ref{app2}).

While many studies explore adaptations in large and long-lived species
to address size-associated cancer problems, few focus on the corollary
consequences. Selection for anticancer mechanisms may act as a
developmental and evolutionary constraint, potentially limiting the
evolutionary trajectory of organisms. This constraint hypothesis is
illustrated by the example of cervical vertebrae numbers in
mammals~\cite{120}.

The mismatch concept, often discussed in the context of recent changes
in human evolution, also extends to natural environmental changes
affecting species (see last section). Species may face natural
mismatches between cancer risks and defenses due to evolving
environmental conditions. Weak cancer defenses may still favor certain
traits if fitness benefits outweigh the associated cancer costs or if
compensatory adaptations evolve to limit these costs. Evolutionary
constraints on anticancer defenses may lead to the evolution of
compensatory fitness mechanisms, possibly explaining phenomena like
menopause in humans and cetaceans~\cite{50}. The hypothesis posits that
traits such as menopause, seen as a mechanism preventing the
proliferation of malignant cells during pregnancies, are more readily
selected than anticancer defenses. This implies that the selection for
anticancer mechanisms presents an evolutionary constraint. The
diversity of compensatory traits in the animal kingdom, when other
cancer-associated traits cannot evolve due to insufficient cancer
defenses, remains largely unexplored.

\subsection{Ecosystem level} 

To comprehend the evolution of anticancer selection, it is essential to
consider the complete ecological context, including the host's
community of organisms (parasites, microbiota) and the broader
ecosystem (predators, competitors). This ecological approach allows a
comprehensive assessment of selective pressures on anticancer
selection. For instance, domesticated species, having often lived in
oncogenic conditions but without the traditional constraints of the
wild (competition, predation, parasitism), might experience a
relaxation of these constraints~\cite{124}. This opens opportunities
for the selection of novel anticancer defenses, as domesticated animals
theoretically have more resources to invest in existing anticancer
mechanisms. The \mbox{maintenance} of costly anticancer defenses is more
likely in a domesticated setting compared to a natural ecosystem with
various natural enemies. The impact of species interactions and the
abiotic environment within ecosystems on the evolution of cancer
avoidance remains largely unexplored but is crucial, considering
species are exposed to these interactions over generations.
Additionally, as most ecosystems are now polluted with mutagenic
substances, the varying vulnerability of species to cancer
initiation/progression, coupled with their ability to evolve cancer
defenses, is likely altering biotic interaction equilibria. This, in
turn, may lead to cascade effects, shaping population dynamics and
communities---an emerging topic in ecology (see last section)
\mbox{(Figure~\ref{fig6}).}\looseness=-1
}

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