Cancer risk across mammals.

Cancer is a ubiquitous disease of metazoans, predicted to disproportionately affect larger, long-lived organisms owing to their greater number of cell divisions, and thus increased probability of somatic mutations1,2. While elevated cancer risk with larger body size and/or longevity has been documented within species3-5, Peto's paradox indicates the apparent lack of such an association among taxa6. Yet, unequivocal empirical evidence for Peto's paradox is lacking, stemming from the difficulty of estimating cancer risk in non-model species. Here we build and analyse a database on cancer-related mortality using data on adult zoo mammals (110,148 individuals, 191 species) and map age-controlled cancer mortality to the mammalian tree of life. We demonstrate the universality and high frequency of oncogenic phenomena in mammals and reveal substantial differences in cancer mortality across major mammalian orders. We show that the phylogenetic distribution of cancer mortality is associated with diet, with carnivorous mammals (especially mammal-consuming ones) facing the highest cancer-related mortality. Moreover, we provide unequivocal evidence for the body size and longevity components of Peto's paradox by showing that cancer mortality risk is largely independent of both body mass and adult life expectancy across species. These results highlight the key role of life-history evolution in shaping cancer resistance and provide major advancements in the quest for natural anticancer defences.

Behavioural ecology meets oncology: quantifying the recovery of animal behaviour to a transient exposure to a cancer risk factor.

Wildlife is increasingly exposed to sublethal transient cancer risk factors, including mutagenic substances, which activates their anti-cancer defences, promotes tumourigenesis, and may negatively impact populations. Little is known about how exposure to cancer risk factors impacts the behaviour of wildlife. Here, we investigated the effects of a sublethal, short-term exposure to a carcinogen at environmentally relevant concentrations on the activity patterns of wild Girardia tigrina planaria during a two-phase experiment, consisting of a 7-day exposure to cadmium period followed by a 7-day recovery period. To comprehensively explore the effects of the exposure on activity patterns, we employed the double hierarchical generalized linear model framework which explicitly models residual intraindividual variability in addition to the mean and variance of the population. We found that exposed planaria were less active compared to unexposed individuals and were able to recover to pre-exposure activity levels albeit with a reduced variance in activity at the start of the recovery phase. Planaria showing high activity levels were less predictable with larger daily activity variations and higher residual variance. Thus, the shift in behavioural variability induced by an exposure to a cancer risk factor can be quantified using advanced tools from the field of behavioural ecology. This is required to understand how tumourous processes affect the ecology of species.

The effect of placentation type, litter size, lactation and gestation length on cancer risk in mammals.

Reproduction is a central activity for all living organisms but is also associated with a diversity of costs that are detrimental for survival. Until recently, the cost of cancer as a selective force has been poorly considered. Considering 191 mammal species, we found cancer mortality was more likely to be detected in species having large, rather than low, litter sizes and long lactation lengths regardless of the placentation types. However, increasing litter size and gestation length are not per se associated with an enhanced cancer mortality risk. Contrary to basic theoretical expectations, the species with the highest cancer mortality were not those with the most invasive (i.e. haemochorial) placentation, but those with a moderately invasive (i.e. endotheliochorial) one. Overall, these results suggest that (i) high reproductive efforts favour oncogenic processes' dynamics, presumably because of trade-offs between allocation in reproduction effort and anti-cancer defences, (ii) cancer defence mechanisms in animals are most often adjusted to align reproductive lifespan, and (iii) malignant cells co-opt existing molecular and physiological pathways for placentation, but species with the most invasive placentation have also selected for potent barriers against lethal cancers. This work suggests that the logic of Peto's paradox seems to be applicable to other traits that promote tumorigenesis.

Polyandry and non-random fertilisation maintain long-term genetic diversity in an isolated island population of adders (Vipera berus).

Conservation genetic theory suggests that small and isolated populations should be subject to reduced genetic diversity i.e., heterozygosity and allelic diversity. Our 34 years study of an isolated island population of adders (Vipera berus) in southern Sweden challenges this notion. Despite a lack of gene flow and a yearly mean estimated reproductive adult population size of only 65 adult adders (range 12-171), the population maintains high levels of heterozygosity and allelic diversity similar to that observed in two mainland populations. Even a 14-year major "bottleneck" i.e., a reduction in adult adder numbers, encompassing at least four adder generations, did not result in any reduction in the island adders' heterozygosity and allelic diversity. Female adders are polyandrous, and fertilisation is non-random, which our empirical data and modelling suggest are underpinning the maintenance of the population's high level of heterozygosity. Our empirical results and subsequent modelling suggest that the positive genetic effects of polyandry in combination with non-random fertilisation, often overlooked in conservation genetic analyses, deserve greater consideration when predicting long-term survival of small and isolated populations.

Transmissible cancers in mammals and bivalves: How many examples are there?: Predictions indicate widespread occurrence.

Transmissible cancers are elusive and understudied parasitic life forms caused by malignant clonal cells (nine lineages are known so far). They emerge by completing sequential steps that include breaking cell cooperation, evade anti-cancer defences and shedding cells to infect new hosts. Transmissible cancers impair host fitness, and their importance as selective force is likely largely underestimated. It is, therefore, crucial to determine how common they might be in the wild. Here, we draw a parallel between the steps required for a transmissible cancer to emerge and the steps required for an intelligent civilisation to emerge in the Milky Way using a modified Drake equation. Using numerical analyses, we estimate the potential number of extant marine and bivalve species in which transmissible cancers might exist. Our results suggest that transmissible cancers are more common than expected, and that new lineages can be found by screening a large number of species.

Transmissible cancer influences immune gene expression in an endangered marsupial, the Tasmanian devil (Sarcophilus harrisii).

Understanding the effects of wildlife diseases on populations requires insight into local environmental conditions, host defence mechanisms, host life-history trade-offs, pathogen population dynamics, and their interactions. The survival of Tasmanian devils (Sarcophilus harrisii) is challenged by a novel, fitness limiting pathogen, Tasmanian devil facial tumour disease (DFTD), a clonally transmissible, contagious cancer. In order to understand the devils' capacity to respond to DFTD, it is crucial to gain information on factors influencing the devils' immune system. By using RT-qPCR, we investigated how DFTD infection in association with intrinsic (sex and age) and environmental (season) factors influences the expression of 10 immune genes in Tasmanian devil blood. Our study showed that the expression of immune genes (both innate and adaptive) differed across seasons, a pattern that was altered when infected with DFTD. The expression of immunogbulins IgE and IgM:IgG showed downregulation in colder months in DFTD infected animals. We also observed strong positive association between the expression of an innate immune gene, CD16, and DFTD infection. Our results demonstrate that sampling across seasons, age groups and environmental conditions are beneficial when deciphering the complex ecoevolutionary interactions of not only conventional host-parasite systems, but also of host and diseases with high mortality rates, such as transmissible cancers.

Transmissible cancer and longitudinal telomere dynamics in Tasmanian devils (Sarcophilus harrisii).

A plethora of intrinsic and environmental factors have been shown to influence the length of telomeres, the protector of chromosome ends. Despite the growing interest in infection-telomere interactions, there is very limited knowledge on how transmissible cancers influence telomere maintenance. An emblematic example of transmissible cancer occurs in the Tasmanian devil (Sarcophilus harrisii), whose populations have been dramatically reduced by infectious cancer cells. To investigate associations between telomere dynamics and the transmissible cancer, we used longitudinal data from a Tasmanian devil population that has been exposed to the disease for over 15 years. We detected substantial temporal variation in individual telomere length (TL), and a positive significant association between TL and age, as well as a marginally significant trend for devils with devil facial tumour disease (DFTD) having longer telomeres. A proportional hazard analysis yielded no significant effect of TL on the development of DFTD. Like previous studies, we show the complexity that TL dynamics may exhibit across the lifetime of organisms. Our work highlights the importance of long-term longitudinal sampling for understanding the effects of wildlife diseases on TL.

Telomeres, the loop tying cancer to organismal life-histories.

Recent developments in telomere and cancer evolutionary ecology demonstrate a very complex relationship between the need of tissue repair and controlling the emergence of abnormally proliferating cells. The trade-off is balanced by natural and sexual selection and mediated via both intrinsic and environmental factors. Here, we explore the effects of telomere-cancer dynamics on life history traits and strategies as well as on the cumulative effects of genetic and environmental factors. We show that telomere-cancer dynamics constitute an incredibly complex and multifaceted process. From research to date, it appears that the relationship between telomere length and cancer risk is likely nonlinear with good evidence that both (too) long and (too) short telomeres can be associated with increased cancer risk. The ability and propensity of organisms to respond to the interplay of telomere dynamics and oncogenic processes, depends on the combination of its tissue environments, life history strategies, environmental challenges (i.e., extreme climatic conditions), pressure by predators and pollution, as well as its evolutionary history. Consequently, precise interpretation of telomere-cancer dynamics requires integrative and multidisciplinary approaches. Finally, incorporating information on telomere dynamics and the expression of tumour suppressor genes and oncogenes could potentially provide the synergistic overview that could lay the foundations to study telomere-cancer dynamics at ecosystem levels.

Can postfertile life stages evolve as an anticancer mechanism?

Why a postfertile stage has evolved in females of some species has puzzled evolutionary biologists for over 50 years. We propose that existing adaptive explanations have underestimated in their formulation an important parameter operating both at the specific and the individual levels: the balance between cancer risks and cancer defenses. During their life, most multicellular organisms naturally accumulate oncogenic processes in their body. In parallel, reproduction, notably the pregnancy process in mammals, exacerbates the progression of existing tumors in females. When, for various ecological or evolutionary reasons, anticancer defenses are too weak, given cancer risk, older females could not pursue their reproduction without triggering fatal metastatic cancers, nor even maintain a normal reproductive physiology if the latter also promotes the growth of existing oncogenic processes, e.g., hormone-dependent malignancies. At least until stronger anticancer defenses are selected for in these species, females could achieve higher inclusive fitness by ceasing their reproduction and/or going through menopause (assuming that these traits are easier to select than anticancer defenses), thereby limiting the risk of premature death due to metastatic cancers. Because relatively few species experience such an evolutionary mismatch between anticancer defenses and cancer risks, the evolution of prolonged life after reproduction could also be a rare, potentially transient, anticancer adaptation in the animal kingdom.

Transmissible cancer and the evolution of sex.

The origin and subsequent maintenance of sex and recombination are among the most elusive and controversial problems in evolutionary biology. Here, we propose a novel hypothesis, suggesting that sexual reproduction not only evolved to reduce the negative effects of the accumulation of deleterious mutations and processes associated with pathogen and/or parasite resistance but also to prevent invasion by transmissible selfish neoplastic cheater cells, henceforth referred to as transmissible cancer cells. Sexual reproduction permits systematic change of the multicellular organism's genotype and hence an enhanced detection of transmissible cancer cells by immune system. Given the omnipresence of oncogenic processes in multicellular organisms, together with the fact that transmissible cancer cells can have dramatic effects on their host fitness, our scenario suggests that the benefits of sex and concomitant recombination will be large and permanent, explaining why sexual reproduction is, despite its costs, the dominant mode of reproduction among eukaryotes.

Is adaptive therapy natural?

Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism's death due to cancer. We propose that organisms' anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body's NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body's NAT and accelerates the evolution of immune resistance.

The evolution of resistance and tolerance as cancer defences.

Although there is a plethora of cancer associated-factors that can ultimately culminate in death (cachexia, organ impairment, metastases, opportunistic infections, etc.), the focal element of every terminal malignancy is the failure of our natural defences to control unlimited cell proliferation. The reasons why our defences apparently lack efficiency is a complex question, potentially indicating that, under Darwinian terms, solutions other than preventing cancer progression are also important contributors. In analogy with host-parasite systems, we propose to call this latter option 'tolerance' to cancer. Here, we argue that the ubiquity of oncogenic processes among metazoans is at least partially attributable to both the limitations of resistance mechanisms and to the evolution of tolerance to cancer. Deciphering the ecological contexts of alternative responses to the cancer burden is not a semantic question, but rather a focal point in understanding the evolutionary ecology of host-tumour relationships, the evolution of our defences, as well as why and when certain cancers are likely to be detrimental for survival.

Oncogenesis as a Selective Force: Adaptive Evolution in the Face of a Transmissible Cancer.

Similar to parasites, malignant cells exploit the host for energy, resources and protection, thereby impairing host health and fitness. Although cancer is widespread in the animal kingdom, its impact on life history traits and strategies have rarely been documented. Devil facial tumour disease (DFTD), a transmissible cancer, afflicting Tasmanian devils (Sarcophilus harrisii), provides an ideal model system to monitor the impact of cancer on host life-history, and to elucidate the evolutionary arms-race between malignant cells and their hosts. Here we provide an overview of parasite-induced host life history (LH) adaptations, then both phenotypic plasticity of LH responses and changes in allele frequencies that affect LH traits of Tasmanian devils in response to DFTD are discussed. We conclude that akin to parasites, cancer can directly and indirectly affect devil LH traits and trigger host evolutionary responses. Consequently, it is important to consider oncogenic processes as a selective force in wildlife.

Urban environment and cancer in wildlife: available evidence and future research avenues.

While it is generally known that the risk of several cancers in humans is higher in urban areas compared with rural areas, cancer is often deemed a problem of human societies with modern lifestyles. At the same time, more and more wild animals are affected by urbanization processes and are faced with the need to adapt or acclimate to urban conditions. These include, among other things, increased exposure to an assortment of pollutants (e.g. chemicals, light and noise), novel types of food and new infections. According to the abundant literature available for humans, all of these factors are associated with an increased probability of developing cancerous neoplasias; however, the link between the urban environment and cancer in wildlife has not been discussed in the scientific literature. Here, we describe the available evidence linking environmental changes resulting from urbanization to cancer-related physiological changes in wild animals. We identify the knowledge gaps in this field and suggest future research avenues, with the ultimate aim of understanding how our modern lifestyle affects cancer prevalence in urbanizing wild populations. In addition, we consider the possibilities of using urban wild animal populations as models to study the association between environmental factors and cancer epidemics in humans, as well as to understand the evolution of cancer and defence mechanisms against it.

Metastasis and the evolution of dispersal.

Despite significant progress in oncology, metastasis remains the leading cause of mortality of cancer patients. Understanding the foundations of this phenomenon could help contain or even prevent it. As suggested by many ecologists and cancer biologists, metastasis could be considered through the lens of biological dispersal: the movement of cancer cells from their birth site (the primary tumour) to other habitats where they resume proliferation (metastatic sites). However, whether this model can consistently be applied to the emergence and dynamics of metastasis remains unclear. Here, we provide a broad review of various aspects of the evolution of dispersal in ecosystems. We investigate whether similar ecological and evolutionary principles can be applied to metastasis, and how these processes may shape the spatio-temporal dynamics of disseminating cancer cells. We further discuss complementary hypotheses and propose experimental approaches to test the relevance of the evolutionary ecology of dispersal in studying metastasis.

Cancer adaptations: Atavism, de novo selection, or something in between?

From an evolutionary perspective, both atavism and somatic evolution/convergent evolution theories can account for the consistent occurrence, and astounding attributes of cancers: being able to evolve from a single cell to a complex organized system, and malignant transformations showing significant similarities across organs, individuals, and species. Here, we first provide an overview of these two hypotheses, including the possibility of them not being mutually exclusive, but rather potentially representing the two extremes of a continuum in which the diversity of cancers can emerge. In reviewing the current literature, we also discuss the criteria that should be applied to discriminate between the two competing theories and to determine their relevant contributions to oncogenesis and cancer progression. Finally, we deliberate on the potential applications of this conceptual framework in developing novel treatment strategies.

How is the evolution of tumour resistance at organ-scale impacted by the importance of the organ for fitness?

BACKGROUND: A strong variability in cancer incidence is observed between human organs. Recently, it has been suggested that the relative contribution of organs to organism fitness (reproduction or survival) could explain at least a part of the observed variation. The objective of this study is to investigate theoretically the main factors driving the evolution of tumour resistance mechanisms of organs when their relative contribution to organism fitness is considered. We use a population-scale model where individuals can develop a tumour in a key organ (i.e. in which even a small tumour can negatively impact organism fitness), an auxiliary organ (i.e. in which only a large tumour has a relatively significant impact) or both organs because of metastasis. RESULTS: Our simulations show that natural selection acts in two different ways to prevent cancer in a key and an auxiliary organs. In the key organ, the strategy mostly selected is the highest resistance and only a high cost of resistance mitigates this behavior. Inversely, we observe that a low resistance strategy can be selected in the auxiliary organ when the development of the tumour is slow and the effect of a large tumour on the mortality of the organism is relatively weak. Nevertheless, if the tumour can spread to a key organ, higher resistance strategies are selected in the auxiliary organ. CONCLUSION: Finally, our study demonstrates that the relative contribution of organs to the organism fitness and the metastatic propensity of the tumour influence the evolution of tumour resistance at organ scale and should be considered by studies aiming to explain the variability in cancer incidence at organ-scale.

Metabolic Scope as a Proximate Constraint on Individual Behavioral Variation: Effects on Personality, Plasticity, and Predictability.

Behavioral ecologists have hypothesized that among-individual differences in resting metabolic rate (RMR) may predict consistent individual differences in mean values for costly behaviors or for behaviors that affect energy intake rate. This hypothesis has empirical support and presently attracts considerable attention, but, notably, it does not provide predictions for individual differences in (a) behavioral plasticity or (b) unexplained variation (residual variation from mean individual behavior, here termed predictability). We outline how consideration of aerobic maximum metabolic rate (MMR) and particularly aerobic scope (= MMR - RMR) can be used to simultaneously make predictions about mean and among- and within-individual variation in behavior. We predict that while RMR should be proportional to an individual's mean level of sustained behavioral activity (one aspect of its personality), individuals with greater aerobic scope will also have greater scope to express behavioral plasticity and/or greater unpredictability in behavior (=greater residual variation). As a first step toward testing these predictions, we analyze existing activity data from selectively bred lines of mice that differ in both daily activity and aerobic scope. We find that replicate high-scope mice are more active on average and show greater among-individual variation in activity, greater among-individual variation in plasticity, and greater unpredictability. These data provide some tentative first support for our hypothesis, suggesting that further research on this topic would be valuable.

Genetic diversity, inbreeding and cancer.

Genetic diversity is essential for adaptive capacities, providing organisms with the potential of successfully responding to intrinsic and extrinsic challenges. Although a clear reciprocal link between genetic diversity and resistance to parasites and pathogens has been established across taxa, the impact of loss of genetic diversity by inbreeding on the emergence and progression of non-communicable diseases, such as cancer, has been overlooked. Here we provide an overview of such associations and show that low genetic diversity and inbreeding associate with an increased risk of cancer in both humans and animals. Cancer being a multifaceted disease, loss of genetic diversity can directly (via accumulation of oncogenic homozygous mutations) and indirectly (via increased susceptibility to oncogenic pathogens) impact abnormal cell emergence and escape of immune surveillance. The observed link between reduced genetic diversity and cancer in wildlife may further imperil the long-term survival of numerous endangered species, highlighting the need to consider the impact of cancer in conservation biology. Finally, the somewhat incongruent data originating from human studies suggest that the association between genetic diversity and cancer development is multifactorial and may be tumour specific. Further studies are therefore crucial in order to elucidate the underpinnings of the interactions between genetic diversity, inbreeding and cancer.

Active migration is associated with specific and consistent changes to gut microbiota in Calidris shorebirds.

Gut microbes are increasingly recognised for their role in regulating an animal's metabolism and immunity. However, identifying repeatable associations between host physiological processes and their gut microbiota has proved challenging, in part because microbial communities often respond stochastically to host physiological stress (e.g. fasting, forced exercise or infection). Migratory birds provide a valuable system in which to test host-microbe interactions under physiological extremes because these hosts are adapted to predictable metabolic and immunological challenges as they undergo seasonal migrations, including temporary gut atrophy during long-distance flights. These physiological challenges may either temporarily disrupt gut microbial ecosystems, or, alternatively, promote predictable host-microbe associations during migration. To determine the relationship between migration and gut microbiota, we compared gut microbiota composition between migrating and non-migrating ("resident") conspecific shorebirds sharing a flock. We performed this across two sandpiper species, Calidris ferruginea and Calidris ruficollis, in north-western Australia, and an additional C. ruficollis population 3,000 km away in southern Australia. We found that migrants consistently had higher abundances of the bacterial genus Corynebacterium (average 28% abundance) compared to conspecific residents (average <1% abundance), with this effect holding across both species and sites. However, other than this specific association, community structure and diversity was almost identical between migrants and residents, with migration status accounting for only 1% of gut community variation when excluding Corynebacterium. Our findings suggest a consistent relationship between Corynebacterium and Calidris shorebirds during migration, with further research required to identify causal mechanisms behind the association, and to elucidate functionality to the host. However, outside this specific association, migrating shorebirds broadly maintained gut community structure, which may allow them to quickly recover gut function after a migratory flight. This study provides a rare example of a repeatable and specific response of the gut microbiota to a major physiological challenge across two species and two distant populations.