The ecology and evolution of wildlife cancers: Applications for management and conservation

Abstract Ecological and evolutionary concepts have been widely adopted to understand host–pathogen dynamics, and more recently, integrated into wildlife disease management. Cancer is a ubiquitous disease that affects most metazoan species; however, the role of oncogenic phenomena in eco‐evolutionary processes and its implications for wildlife management and conservation remains undeveloped. Despite the pervasive nature of cancer across taxa, our ability to detect its occurrence, progression and prevalence in wildlife populations is constrained due to logistic and diagnostic limitations, which suggests that most cancers in the wild are unreported and understudied. Nevertheless, an increasing number of virus‐associated and directly transmissible cancers in terrestrial and aquatic environments have been detected. Furthermore, anthropogenic activities and sudden environmental changes are increasingly associated with cancer incidence in wildlife. This highlights the need to upscale surveillance efforts, collection of critical data and developing novel approaches for studying the emergence and evolution of cancers in the wild. Here, we discuss the relevance of malignant cells as important agents of selection and offer a holistic framework to understand the interplay of ecological, epidemiological and evolutionary dynamics of cancer in wildlife. We use a directly transmissible cancer (devil facial tumour disease) as a model system to reveal the potential evolutionary dynamics and broader ecological effects of cancer epidemics in wildlife. We provide further examples of tumour–host interactions and trade‐offs that may lead to changes in life histories, and epidemiological and population dynamics. Within this framework, we explore immunological strategies at the individual level as well as transgenerational adaptations at the population level. Then, we highlight the need to integrate multiple disciplines to undertake comparative cancer research at the human–domestic–wildlife interface and their environments. Finally, we suggest strategies for screening cancer incidence in wildlife and discuss how to integrate ecological and evolutionary concepts in the management of current and future cancer epizootics.

tions, which suggests that most cancers in the wild are unreported and understudied.
Nevertheless, an increasing number of virus-associated and directly transmissible cancers in terrestrial and aquatic environments have been detected. Furthermore, anthropogenic activities and sudden environmental changes are increasingly associated with cancer incidence in wildlife. This highlights the need to upscale surveillance efforts, collection of critical data and developing novel approaches for studying the emergence and evolution of cancers in the wild. Here, we discuss the relevance of malignant cells as important agents of selection and offer a holistic framework to understand the interplay of ecological, epidemiological and evolutionary dynamics of cancer in wildlife. We use a directly transmissible cancer (devil facial tumour disease) as a model system to reveal the potential evolutionary dynamics and broader ecological effects of cancer epidemics in wildlife. We provide further examples of tumour-host interactions and trade-offs that may lead to changes in life histories, and epidemiological and population dynamics. Within this framework, we explore immunological strategies at the individual level as well as transgenerational adaptations at the population level. Then, we highlight the need to integrate multiple disciplines to undertake comparative cancer research at the human-domestic-wildlife interface and their environments. Finally, we suggest strategies for screening cancer incidence in wildlife and discuss how to integrate ecological and evolutionary concepts in the management of current and future cancer epizootics.

| INTRODUC TI ON
Over the last two decades, significant efforts have been made to incorporate ecological and evolutionary principles to better understand the dynamics of wildlife diseases and their impact on wild populations (Galvani, 2003;Tompkins, Dunn, Smith, & Telfer, 2011;Vander Wal et al., 2014). The reciprocal interactions between host and pathogens are in many ways analogous to the interplay of ecological and evolutionary processes between species and their environment. Thus, the eco-evolutionary processes and feedbacks in emerging host-pathogen systems are currently considered key in epidemiology and disease management (Brosi, Delaplane, Boots, & Roode, 2017;Coen & Bishop, 2015;Grenfell et al., 2004). Cancer is a disease that evolved with the transition to multicellularity (Aktipis & Nesse, 2013) and therefore affects most metazoans on earth. It corresponds to a family of potentially lethal pathologies in which normal cells lose their typical cooperative behaviour, proliferate, spread and hence become malignant. Despite the ubiquitous nature of cancers in wildlife, the role of the oncobiota (i.e. oncogenic phenomena from precancerous lesions to metastatic cancer, Thomas et al., 2017) in ecological and evolutionary processes has been historically neglected (but see Thomas et al., 2017;Vittecoq et al., 2013) and its applications for wildlife management and conservation remain mostly in their infancy. Given that cancer is an evolving disease where the ecological context of tumour-host interactions is of paramount relevance for disease progression and immunological responses, evolutionary principles have recently been used in oncology as a novel approach for developing therapeutic treatments (Enriquez-Navas, Wojtkowiak, & Gatenby, 2015;Willyard, 2016;Zhang, Cunningham, Brown, & Gatenby, 2017).
Oncogenic phenomena can act as important agents of selection by having differential effects on the survival, life history, reproductive success and fitness of hosts Ujvari, Beckmann, et al., 2016). These processes can shape phenotypic, genetic and epigenetic variance across individuals, populations and species. Carcinogenesis is a complex process that depends on trade-offs at the cellular and organismal levels, and, in turn, these trade-offs interact with individuals and species, and hence ecosystems Pesavento, Agnew, Keel, & Woolard, 2018;Wu, Wang, Ling, & Lu, 2016). Thus, cancer should not be studied in isolation but as an interacting force of selection between species and their changing environments. Furthermore, in a century characterized by rapid environmental changes, species are increasingly facing additional ecological and immunological trade-offs that in turn may increase cancer risk . Unravelling the synergistic effects of environmental degradation, ecological and evolutionary processes, and susceptibility to cancer is nonetheless a complex task. Recognizing these complexities using a multidisciplinary approach will permit the understanding of important concepts underpinning cancer emergence and evolution and at the same time identify novel and integrative frameworks for managing cancers in wildlife.
The misleading assumption that cancers in wildlife are rare stems from the logistic difficulties in detecting their occurrence and monitoring their prevalence: in most cases, afflicted hosts are preyed upon or die unseen (Vittecoq et al., 2013). This suggests that most cancers in the wild are unreported and understudied. In addition, infectious agents are now well recognized as important drivers of cancer causation. For example, 15%-20% of all cancers in humans have been associated with a direct infectious origin (i.e. oncoviruses) (Alizon, Bravo, Farrell, & Roberts, 2019;Ewald & Swain Ewald, 2015).
There is considerable evidence that environmental factors are a major contributor to cancer risk. Anthropogenic activities such as urbanization, chemical contamination and knock-on effects from rapid environmental changes have been associated with high cancer prevalence in wildlife and a lack of upregulation of anticancer defence mechanisms in these carcinogenic habitats (Giraudeau, Sepp, Ujvari, Ewald, & Thomas, 2018;Giraudeau et al., 2020;Pesavento et al., 2018;Sepp, Ujvari, Ewald, Thomas, & Giraudeau, 2019). However, only recently has cancer been considered a disease of conservation concern (McAloose & Newton, 2009) and transmissible cancers regarded as a new modality of infectious disease . The increasing number of virus-associated and directly transmitted cancers detected in wildlife (Table 1), particularly for species already endangered (Gulland, Trupkiewicz, Spraker, & Lowenstine, 1996;James et al., 2019;McCallum et al., 2009;Williams et al., 1994;Woolford et al., 2008), demonstrates the urgent need for developing a holistic framework for studying oncogenic phenomena in the wild. Studying patterns of emergence, tumour-host interactions and evolutionary processes between hosts and malignant cells will also provide new insights into our understanding of how cancer defence mechanisms arise and evolve in nature (Nunney, 2013).

| IMMUNE RE S P ON S E S TO INFEC TI OUS C AN CER S IN WILDLIFE
Infectious cancers can be broadly grouped into two categories: directly transmissible cancers, where the infectious agent is the cancer cell itself (Ostrander, Davis, & Ostrander, 2016), and indirectly transmissible cancers, where the infectious agent is a pathogen such as a virus that induces cancer formation (Ewald & Swain Ewald, 2015).
Although there are similarities in terms of host immune responses, the interaction between these types of infectious cancers with the host immune system is multifaceted and in some cases cancer-specific, as described in detail below. The vertebrate immune system consists of two arms: the innate immune system, which functions to induce systemic inflammation and nonspecific immune responses (Hato & Dagher, 2015), and the adaptive immune system, which exerts specific immune responses against pathogens or tumour-associated antigens (Cooper & Alder, 2006). Understanding the interaction between infectious cancers and the host immune system is key to developing effective disease management strategies.
Low polymorphism has been linked to reduced species fitness and a lower ability to recognize novel pathogens (  TA B L E 1 (Continued) Tovar et al., 2017). It is unclear whether marine bivalves raise any immune response against their transmissible neoplasia, although the lack of an adaptive immune system and MHC in invertebrates suggests that they may be more vulnerable to direct transmission of cancerous cell lines (Gestal et al., 2008;. At least until stronger anticancer defences (resistance) are selected for in these species, individuals could potentially achieve higher fitness by increasing their tolerance to cancer, that is surviving despite the presence of tumours .
Further studies would be necessary to test this hypothesis and to determine the extent to which the ecological and evolutionary drivers of tumour suppressor gene expression observed in certain vertebrates (i.e. elephants, see Abegglen et al., 2015) are also relevant in invertebrates. Currently, there is no empirical evidence for an exogenous initiator for any clonally transmissible cancers Murchison et al., 2012Murchison et al., , 2014Stammnitz et al., 2018). A promising direction worth to explore in light of the increasing number of transmissible cancers Ujvari, Beckmann, et al., 2016;Ujvari Gatenby, & Thomas, 2016bb) is to determine the contribution of the immune system complexity to the emergence of contagious malignant cell lines and whether transmissible tumours have an immune cell originator.

| Indirectly transmissible cancers
There  (King et al., 2002), there is a strong correlation between environmental organochlorine contamination and cancer incidence despite equivalent OtHV-1 infection rates (Randhawa, Gulland, Ylitalo, DeLong, & Mazet, 2015). A link has also been demonstrated between MHC diversity and cancer risk (Bowen et al., 2005), indicating a genetic component to the disease that mirrors the emergence of directly transmissible tumours .
The ceruminous gland tumours affecting the Santa Catalina Island fox (Urocyon littoralis catalinae) are associated with ear mite infestations, and a generalized systemic inflammatory environment caused by bite wounds combined with a specific immune response to ear mite infection is thought to encourage tumour formation (Moriarty et al., 2015;Vickers et al., 2015). Similar mechanisms have been suggested in the emergence and transmission of facial tumours in the Tasmanian devil due to their aggressive social interactions (Hamede, McCallum, & Jones, 2013;Stammnitz et al., 2018).
The complex underlying causes of infectious cancers caused by pathogens often result in a systemic and nonspecific immune response that is not protective, causing chronic infection and tumour persistence (Browning, Gulland, Hammond, Colegrove, & Hall, 2015;Moriarty et al., 2015). One common feature that may underpin the emergence of directly and indirectly transmissible cancers is low genetic diversity, as evidenced by Tasmanian devils (Siddle, Kreiss, et al., 2007), Santa Catalina Island foxes (Hofman et al., 2015) and California sea lions (Acevedo-Whitehouse, Gulland, Greig, & Amos, 2003). However, many wild populations with extremely low genetic diversity thrive without increased cancer incidence (Weber, Stewart, Schienman, & Lehman, 2004), indicating that genetic diversity cannot alone be causative and that more complex interactions may be responsible for carcinogenesis. Although strong associations exist between pathogens and indirectly transmissible tumours, most infected individuals do not develop cancer, indicating that infection alone is not entirely the cause of tumour growth (Rehtanz et al., 2010;Vickers et al., 2015).
Infectious cancers are the result of complex combinations of genetic susceptibility, pathogenic infections, and abiotic and behavioural factors that allow the emergence and transmission of tumour cells or pathogens between individuals (i.e. the "perfect storm," see Ujvari, Beckmann, et al., 2016;Ujvari Gatenby, & Thomas, 2016aa). Understanding the interplay between these risk factors during the emergence and spread of cancers that are either caused by pathogens or by contagious cancer cell lines will not only help in managing current epidemics but also help to identify and manage emerging epidemics before they become widespread.

| ECOLOG I C AL , EPIDEMI OLOG I C AL AND E VOLUTIONARY DYNAMIC S OF C AN CER S IN WILDLIFE
Cancer emergence and progression do not occur in a vacuum, but rather in a complex suite of ecological and evolutionary interactions.
In the same way that hosts can compensate for the fitness effects of parasitic infections (i.e. phenotypic plasticity of life-history traits), cancer is expected to trigger host responses to cope with the immunological and physiological demands of growing tumours. The diverse effects of cancer in host fitness (i.e. vulnerability to predation, susceptibility to coinfection with other pathogens, limited reproductive output, reduced ability to disperse) often result in host responses and adaptive processes early in cancer development.
For example, an experimental study demonstrated that drosophila (D. melanogaster) with induced colorectal cancer are able to adjust their life-history traits by reaching the peak of oviposition significantly earlier that healthy ones (Arnal et al., 2017). Furthermore, there is evidence that the social environment of hosts can have a significant impact on cancer progression. Drosophila with induced colorectal cancer had faster tumour growth rates when kept in isolation than did flies in control groups (Dawson et al., 2018). These responses demonstrate the intricate and dynamic relationships between hosts and oncogenic processes and the ability of hosts to trade off fitness costs at different stages of disease. Likewise, host social structure, behaviour and sexual selection have the potential to affect contact rates and hence the transmission of infectious cancers (Vittecoq et al., 2015).  (Das & Das, 2000). Although CTVT may have been highly lethal early in its evolutionary history (see also Leathlobhair et al., 2018), it now coexists with its hosts (Strakova & Murchison, 2015). Coexistence between dogs and CTVT might be the result of continuous selective processes between the cancer cell line and hosts over millennia.
However, the strong selective pressures of cancer can also operate on extremely short time scales. For example, a small proportion of Tasmanian devils have developed immune responses to DFTD resulting in natural tumour regressions in as little as 8-10 years (4-5 generations) after the cancer epidemic (Pye, Hamede, et al., 2016).
The extremely high mortality of DFTD and the subsequent catastrophic population declines resulted in selection in regions of the genome that are associated with immune function and cancer risk (Epstein et al., 2016). More importantly, the evolutionary dynamics in the tumour can affect individuals and populations in different contexts. As the DFTD epidemic unfolded, a sudden local replacement of tumour karyotype (from tetraploid to diploid) resulted in a significant increase of infection rates and population decline (Hamede et al., 2015). Observed differential growth rates between tetraploid and diploid tumours (Hamede, Beeton, Carver, & Jones, 2017) may also select for polymorphism in tumour virulence. This may provide scope for an evolutionary arms race between cancer cells and hosts. At the host level, a broad range of eco-immunological dynamics such as seasonal dynamics of stress, demographic variation in immune expression profiles, reproductive hormones and immune senescence, as well as genetic and phenotypic variation, may interact with cancer susceptibility and tumour progression. At the tumour level, selection should favour lineages that reach optimal virulence, a trade-off between transmission rate and disease-induced mortality (Ebert & Bull, 2003).
The Tasmanian devil-DFTD system provides a unique opportunity to understand the interplay of ecological, evolutionary and epidemiological dynamics in response to cancer (Figure 1). Both tu-

| FOLLOWING THE C AN CER FOOTPRINT: FROM S PECIE S CON S ERVATI ON TO ECOSYS TEM FUN C TI ON
Cancer may be of particular concern in the small population paradigm in conservation, where stochastic causes of mortality can present a significant threat. Small populations or threatened species with low genetic diversity might be more susceptible to cancer . Population-level effects of cancer, such as reduction in population growth rate and cascading effects flowing through community and ecosystem levels, can be difficult to document. Establishing causal links between population decline and oncogenic processes in wildlife is fraught with the difficulties of long-term investigation and establishing the cause of mortalities in a sufficient proportion of the population. The clearest and best documented case of population decline caused by cancer is the Tasmanian devil-DFTD system (see Box 1).
Genetically isolated populations or those affected by other threatening processes can become more susceptible to cancer or mutagenic agents. For example, the critically endangered Santa Catalina Island fox neared extinction from hyperpredation by native eagles facilitated by abundant feral pigs (Roemer, Coonan, Garcelon, Bascompte, & Laughrin, 2001). Santa Catalina island foxes are also highly susceptible to exotic diseases (Crooks, Scott, & Vuren, 2001) and to ceruminous gland tumours, for which chronic inflammation from bacterial and mite infestation may promote tumorigenesis . The genetic distinctiveness of this subspecies may predispose it to cancer: it has one of the highest rates of cancer observed in a wild population . Documented evidence of trophic cascades triggered by cancer-induced population decline is rare and often not known (e.g. Santa Catalina Island fox; Vickers et al., 2015). Again, the Tasmanian devil-DFTD host-pathogen system provides the clearest and best documented case study. The progressive spatial and temporal patterns of devil population decline as DFTD has spread from east to west across the island state provide a rare natural experiment on the influential top-down role of this apex predator and primary scavenger in structuring Tasmanian ecosystems (Hollings, Jones, Mooney, & McCallum, 2014, 2016. The decline in devil populations has released invasive mesopredators from competition, with cascading effects on the decline in populations of small native mammals (Hollings, Jones, Mooney, & McCallum, 2016). Introduced pest species such feral cats (Felis catus) and black rats (Rattus rattus) have increased in abundance (Cunningham et al., 2018). While the native mesopredator, the spotted-tailed quoll (Dasyurus maculatus), relax their temporal avoidance of devils when devils are at low density (Cunningham, Scoleri, Johnson, Barmuta, & Jones, 2019), it is possible that competition with the similar-sized feral cat, which has a higher fecundity (two rather than one litter per year), may counter the competitive release F I G U R E 1 The Tasmanian devil and its transmissible tumour (DFTD), an ideal model system to understand how species adapt and evolve in response to infectious cancers and study the interplay of ecological, evolutionary and epidemiological processes. Blue boxes represent host and tumour parameters under selection through evolutionary interactions (red arrows). Host tolerance and resistance and tumour morbidity and virulence are under selection through ecological and evolutionary interactions. These interactions feed back into epidemiological and population dynamics (green arrows)  (Hollings, Jones, Mooney, & McCallum, 2013). These processes at the species and ecosystem levels highlight the broadscale effects of cancer in wildlife and the vital need to document and study its implications for ecosystem functioning.

| APPLI C ATI ON S FOR MANAG EMENT AND CONS ERVATION
Studies of cancer in wildlife have been mostly accidental and reactive.
There has been a historical lack of consistency in studying tumorigen-

Box 1. The birth, spread and impact of transmissible cancers in Tasmanian devils
First detected in 1996 in northeast Tasmania, DFTD has spread across most of the distributional range of the devil in Tasmania ( Figure 2; Hawkins et al., 2006;Lazenby et al., 2018). Clearly visible primary tumours (Loh et al., 2006), high recapture probability in trapping surveys , and a concerted field monitoring and research effort have enabled clear causal links between DFTD spread, population decline and cascading effects at the ecosystem level to be established (Lazenby et al., 2018;McCallum et al., 2007).
Devil population decline accelerates 3 years after local disease emergence because the infection increases exponentially , reaching a 60% decline after 5-6 years and up to a 90% decline in some areas McCallum et al., 2007). The rapid population decline led to the species being listed as Endangered at the international (IUCN Red List), national and state levels (Hawkins, McCallum, Mooney, Jones, & Holdsworth, 2009). Strong frequency-dependent transmission, likely caused by biting during the mating season, also contributed to concerns of extinction as a possible outcome of the epidemic ). However, to date, no local extinctions have been reported and long-term diseased populations persist despite high prevalence of tumours (Hamede et al., 2015;Lazenby et al., 2018). The rapid evolutionary response of devils to DFTD (within 4-6 generations) indicates that the adaptive shift is operating on the genetic variation present prior to the DFTD epidemic (Epstein et al., 2016), despite the low genetic diversity (Jones, Paetkau, Geffen, & Moritz, 2004;Siddle, Marzec, Cheng, Jones, & Belov, 2010)  In 2014, a second and independently evolved transmissible cancer (DFT2) was discovered at the d'Entrecasteaux peninsula in southeastern Tasmania. DFT2 and DFTD coexist in the same population, and a limited number cases of coinfection (both diseases in the same individual) have been reported . Both tumours have been reported to be of neuroectodermal origin and most likely evolved from devils in north-eastern and south-eastern Tasmania Storfer et al., 2018). So far, DFT2 seems to be confined to the peninsula where it was first reported, although monitoring efforts outside of the peninsula have been limited . The population response to DFT2 and the epidemiological, ecological and evolutionary interactions between devils and DFTD are currently unknown; however, competition and selective processes are expected to occur at individual and population levels. In that sense, current and future research will be vital to predict epidemiological and evolutionary dynamics in the devil/DFTD/DFT2 study system. mitigate risks of cancer emergence in the wild. We therefore suggest using a three-level approach to the study of wildlife cancer that will provide a solid link between fundamental research in cancer biology, eco-evolutionary processes and management and conservation. Evaluating the role of infectious cancers as important agents of selection across populations provides a holistic and adaptive framework for understanding the adaptive capabilities of different species in response to oncogenic processes . The integration of these disciplines will also help to disentangle the biological/environmental mechanisms of cancer emergence and evaluate the diversity and lethality of tumours across taxa.
Finally, the knowledge generated from the cross-discipline framework should be used to develop adaptive management strategies and general guidelines in response to infectious cancers in wildlife. For example, understanding the long-term effects of the DFTD epidemic in Tasmanian

CO N FLI C T O F I NTE R E S T
None declared.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analysed in this study.