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.

Natural Selection, The Microbiome, and Public Health.

The microbiome is composed of hundreds of interacting species that have co-evolved with the host and alterations in microbiome composition have been associated with health and disease. Insights from evolutionary ecology may aid efforts to ameliorate microbiome-associated diseases. One step toward this goal involves recognition that the idea of commensalism has been applied too broadly to human/microbe symbioses. Commensalism is most accurately viewed on a symbiosis continuum as a dividing line that separates a spectrum of mutualisms of decreasing positive interdependence from parasitisms of increasing severity. Insights into the evolution of the gut microbial symbiosis continuum will help distinguish between human actions that will advance or hinder health. Theory and research indicate that a major benefit of mutualistic microbes will be protection against pathogens. Mismatches between current and ancestral diets may disfavor mutualists, resulting in microbiome effects on health problems, including obesity, diabetes, autism, and childhood allergy. Evolutionary theory indicates that mutualisms will be favored when symbionts depend on resources that are not used by the host. These resources, which are referred to as human-inaccessible microbiota-accessible carbohydrates (HIMACs), can be supplied naturally through diet. Public health interventions need to consider the position of gut microbes on the mutualist-parasite continuum and the specific associations between prebiotics, such as HIMACs, and the mutualists they support. Otherwise interventions may fail to restore the match between human adaptations, diet, and microbiome function and may thereby fail to improve health and even inadvertently promote illness.

An evolutionary perspective on the causes and treatment of inflammatory bowel disease.

PURPOSE OF REVIEW: To use insights from evolutionary biology to assess the current evidence for the causes, treatment, and prevention of inflammatory bowel disease (IBD). RECENT FINDINGS: When analyzed in the context of evolutionary adaptation, recent assessments of genetic, microbial, and environmental associations with IBD implicate infectious causation. SUMMARY: An evolutionary perspective provides insight into the causes of IBD, interpretation of its manifestations, and assessment of interventions. The evidence implicating infectious causation suggests that future studies of IBD would benefit from increased focus on infectious causes and interventions that prevent or inhibit them.

Evolution of virulence, environmental change, and the threat posed by emerging and chronic diseases.

Assessments of future threats posed by infection have focused largely on zoonotic, acute disease, under the rubric "emerging diseases." Evolutionary and epidemiological studies indicate, however, that particular aspects of infrastructure, such as protected water supplies, vector-proof housing, and health care facilities, protect against the emergence of zoonotic, acute infectious diseases. While attention in the global health community has focused on emerging diseases, there has been a concurrent, growing recognition that important chronic diseases, such as cancer, are often caused by infectious agents that are already widespread in human populations. For economically prosperous countries, the immediacy of this threat contrasts with their infrastructural protection from severe acute infectious disease. This reasoning leads to the conclusion that chronic infectious diseases pose a more significant threat to economically prosperous countries than zoonotic, acute infectious diseases. Research efforts directed at threats posed by infection may therefore be more effective overall if increased efforts are directed toward understanding and preventing infectious causes of chronic diseases across the spectrum of economic prosperity, as well as toward specific infrastructural improvements in less prosperous countries to protect against virulent, acute infectious diseases.

The evolution of barriers to exploitation: Sometimes the Red Queen can take a break.

We propose a general barrier theory as an evolutionary framework for understanding coevolutionary effects of conflicts of interest in natural and human systems. It is generalized from the barrier theory of cancer, which describes how cancer develops through the evasion of mechanisms, that block unregulated cellular reproduction and survival. Barriers are naturally evolved or artificially implemented mechanisms for blocking exploitation; restraints are mechanisms that impede but do not block exploitation. When conflicts of interest arise, selection will favor exploiters that are capable of overcoming barriers and restraints. When barriers are in place, they halt, at least temporarily, coevolutionary arms races (the Red Queen can stop running). Barriers occur in a broad spectrum of interactions characterized by conflicts of interest: barriers to cellular survival (apoptosis) and reproduction (cell cycle arrest) may block a virus from replicating its genome through reproduction of its host cell. Vaccines may completely protect against targeted pathogens. A plant may escape herbivory by evolving defensive chemicals that block herbivory. Obligate mutualisms may evolve when barriers to horizontal transmission favor symbionts that increasingly lose mechanisms that contribute to horizontal transmission. Here, we show how the barrier theory applies across a spectrum of natural and social systems.

An evolutionary perspective on parasitism as a cause of cancer.

For the past half-century, the dominant paradigm of oncogenesis has been mutational changes that disregulate cellular control of proliferation. Parasitic causes of cancer were first incorporated into this paradigm by suggesting mechanisms through which parasitism might increase mutational damage, such as generation of mutagenic compounds during immunological activity. The growing recognition of the molecular mechanisms of pathogen-induced oncogenesis and the difficulty of generating oncogenic mutations without first having large populations of dysregulated cells, however, suggests that pathogens, particularly viruses, are major initiators of oncogenesis for many if not most cancers, and that the traditional mutation-driven process becomes the dominant process after this initiation. Molecular phylogenies of individual cancers should facilitate testing of this idea and the identification of causal pathogens.

The scope of viral causation of human cancers: interpreting virus density from an evolutionary perspective.

Most known oncogenic viruses of humans use DNA as their genomic material. Research over the past quarter century has revealed that their oncogenicity results largely from direct interference with barriers to oncogenesis. In contrast to viruses that have been accepted causes of particular cancers, candidate viral causes tend to have fewer viral than cellular genomes in the tumours. These low viral loads have caused researchers to conclude that the associated viruses are not primary causes of the associated cancers. Consideration of differential survival, reproduction and infiltration of cells in a tumour suggest, however, that viral loads could be low even when viruses are primary causes of cancer. Resolution of this issue has important implications for human health because medical research tends to be effective at preventing and controlling infectious diseases. Mathematical models may clarify the problem and help guide future research by assessing whether low viral loads are likely outcomes of the differential survival, reproduction, and infiltration of cells in a tumour and, more generally, the extent to which viruses contribute to cancer. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.

Inflammation, infection and depression: an evolutionary perspective.

The evolutionary basis for clinical depression is not well understood. A growing body of literature that is not based on evolutionary logic links inflammation to depression. Integration of these findings with an evolutionary framework for depression, however, needs to address the reasons why the body's inflammatory response would be regulated so poorly that it would result in incapacitating depression. Pathogen induction of inflammation offers an explanation, but the extent to which the association between inflammation and depression can be attributed to general inflammation as opposed to particular effects of pro-inflammatory pathogens remains unclear. This paper reports a study of sexually transmitted pathogens, which addresses this issue. Although several sexually transmitted pathogens were associated with depression according to bivariate tests, only Chlamydia trachomatis and Trichomonas vaginalis were significantly associated with depression by a multivariate analysis that accounted for correlations among the pathogens. This finding is consistent with the hypothesis that infection may contribute to depression through induction of tryptophan restriction, and a consequent depletion of serotonin. It reinforces the idea that some depression may be caused by specific pathogens in specific evolutionary arms races with their human host.

Ancient cancers and infection-induced oncogenesis.

Cancers have been reported in bone and soft tissue of ancient agricultural populations. Fossilized bones from prehistoric periods provide evidence of tumors but only one example of cancer. Difficulties in diagnosing the causes of lesions in mummified tissue and fossilized bone, and in interpreting the prevalence of cancers from remains, draw attention to the need for complementary approaches to assess the occurrence of cancer in ancient populations. This paper integrates current knowledge about pathogen induction of cancer with phylogenetic analyses of oncogenic pathogens, and concludes that pathogen-induced cancers were probably generally present in ancient historic and prehistoric human populations. Consideration of cancers in extant human populations and wildlife lends credence to this conclusion, with the caveat that the presence of cancers may depend on population-specific exposures to oncogenic parasites and carcinogens.

Human activities might influence oncogenic processes in wild animal populations.

Based on the abundant studies available on humans showing clear associations between rapid environmental changes and the rate of neoplasia, we propose that human activities might increase cancer rate in wild populations through numerous processes. Most of the research on this topic has concentrated on wildlife cancer prevalence in environments that are heavily contaminated with anthropogenic chemicals. Here, we propose that human activities might also increase cancer rate in wild populations through additional processes including light pollution, accidental (for example, human waste) or intentional (for example, bird feeders) wildlife feeding (and the associated change of diet), or reduction of genetic diversity in human-impacted habitats. The human species can thus be defined as an oncogenic species, moderating the environment in the way that it causes cancer in other wild populations. As human impacts on wildlife are predicted to increase rather than decrease (for example, in the context of urbanization), acknowledging the possible links between human activity and cancer in wild populations is crucial.

Infection and cancer in multicellular organisms.

Evolutionary considerations suggest that oncogenic infections should be pervasive among animal species. Infection-associated cancers are well documented in humans and domestic animals, less commonly reported in undomesticated captive animals, and rarely documented in nature. In this paper, we review the literature associating infectious agents with cancer to evaluate the reasons for this pattern. Non-malignant infectious neoplasms occur pervasively in multicellular life, but oncogenic progression to malignancy is often uncertain. Evidence from humans and domestic animals shows that non-malignant infectious neoplasms can develop into cancer, although generally with low frequency. Malignant neoplasms could be difficult to find in nature because of a low frequency of oncogenic transformation, short survival after malignancy and reduced survival prior to malignancy. Moreover, the evaluation of malignancy can be ambiguous in nature, because criteria for malignancy may be difficult to apply consistently across species. The information available in the literature therefore does not allow for a definitive assessment of the pervasiveness of infectious cancers in nature, but the presence of infectious neoplasias and knowledge about the progression of benign neoplasias to cancer is consistent with a widespread but largely undetected occurrence.

Sexually Transmitted Pathogens, Depression, and Other Manifestations Associated with Premenstrual Syndrome.

This study investigated whether sexually transmitted infections and lifestyle variables are associated with premenstrual syndrome (PMS) as well as particular manifestations commonly associated with PMS. Data were gathered from medical records of 500 regularly cycling women. The following infectious agents were investigated: human papillomavirus, Chlamydia trachomatis, Neisseria gonorrheae, Gardnerella vaginalis, Candida albicans, and Trichomonas vaginalis. Bivariate tests and multivariate logistic regressions were used to evaluate whether these pathogens were associated with headache, pain, nausea, and depression. Chlamydia trachomatis was significantly associated with premenstrual syndrome (PMS) and two common manifestations of PMS: depression and pain. Trichomonas vaginalis was significantly correlated with headache and Gardnerella vaginalis with nausea. None of the illness manifestations was significantly associated with the tested lifestyle variables: dietary calcium supplementation, alcohol and drug use, exercise, and smoking. These associations provide a basis for assessment of infectious causation of PMS and several manifestations of illness that are commonly associated with PMS.

Evolutionary perspective of cancer: myth, metaphors, and reality.

The evolutionary perspective of cancer (which origins and dynamics result from evolutionary processes) has gained significant international recognition over the past decade and generated a wave of enthusiasm among researchers. In this context, several authors proposed that insights into evolutionary and adaptation dynamics of cancers can be gained by studying the evolutionary strategies of organisms. Although this reasoning is fundamentally correct, in our opinion, it contains a potential risk of excessive adaptationism, potentially leading to the suggestion of complex adaptations that are unlikely to evolve among cancerous cells. For example, the ability of recognizing related conspecifics and adjusting accordingly behaviors as in certain free-living species appears unlikely in cancer. Indeed, despite their rapid evolutionary rate, malignant cells are under selective pressures for their altered lifestyle for only few decades. In addition, even though cancer cells can theoretically display highly sophisticated adaptive responses, it would be crucial to determine the frequency of their occurrence in patients with cancer, before therapeutic applications can be considered. Scientists who try to explain oncogenesis will need in the future to critically evaluate the metaphorical comparison of selective processes affecting cancerous cells with those affecting organisms. This approach seems essential for the applications of evolutionary biology to understand the origin of cancers, with prophylactic and therapeutic applications.

Timing of transmission and the evolution of virulence of an insect virus.

We used the nuclear polyhedrosis virus of the gypsy moth, Lymantria dispar, to investigate whether the timing of transmission influences the evolution of virulence. In theory, early transmission should favour rapid replication and increase virulence, while late transmission should favour slower replication and reduce virulence. We tested this prediction by subjecting one set of 10 virus lineages to early transmission (Early viruses) and another set to late transmission (Late viruses). Each lineage of virus underwent nine cycles of transmission. Virulence assays on these lineages indicated that viruses transmitted early were significantly more lethal than those transmitted late. Increased exploitation of the host appears to come at a cost, however. While Early viruses initially produced more progeny, Late viruses were ultimately more productive over the entire duration of the infection. These results illustrate fitness trade-offs associated with the evolution of virulence and indicate that milder viruses can obtain a numerical advantage when mild and harmful strains tend to infect separate hosts.

Evolution of virulence.

At the close of the 19th century, the germ theory had generated a new understanding of the causes of acute infectious diseases and revealed new directions for study. This understanding contributed to the greatest improvements in health in the history of medicine. At the end of the 20th century, the second stage of this disciplinary development is occurring. The old germ theory is being expanded into a new germ theory, which, by integrated the full spectrum of biologic disciplines. This new germ theory is emphasizing how environments and human activities influence the characteristics of infectious agents and the broader role of infection as a cause of chronic diseases.

Cost of territory establishment in hummingbirds.

Time spent in territorial defense was measured during territory establishment for non-breeding Black-chinned (Archilochus alexandri) and Anna's (Calypte anna) hummingbirds. Newly established territory holders spent more time chasing intruders than neighboring established owners, which served as controls. This higher investment in defense by the new owners was due to 1) a longer time spent per each chase and 2) in some cases, a higher frequency of chases at the onset of territory ownership.

Territorial responses to energy manipulations in the Anna hummingbird.

Territorial activity in the Anna hummingbird (Calypte anna) was measured while energy availability on the territory was varied. On days when energy availability was unlimited, residents defended highly exclusive territories primarily by energetically expensive defense behaviors. As energy availability decreased, exclusiveness declined gradually, relative use of energetically inexpensive defense increased, and owners spent less time on the territory.Territorial behavior also varied with short term depressions in energy availability: A lower percentage of intruders was chased and departures of an owner from its territory were more frequent shortly after feeding.When resource dispersion was increased without changing substantially total rewards per territory, chasing by owners increased.

Mobility of Impatiens capensis flowers: effect on pollen deposition and hummingbird foraging.

Flexible pedicels are characteristic of birdpollinated plants, yet have received little attention in studies of hummingbird-flower interactions. A major implication of flexible pedicels is that flowers may move during pollination. We examined whether such motion affected interactions between ruby-throated hummingbirds (Archilochus colubris) and jewelweed (Impatiens capensis) by increasing pollen deposition and by altering the effectiveness of nectar removal. For I. capensis, flower mobility enhanced pollen deposition: birds had significantly longer contact with anthers and more pollen deposited on their bills and crowns when foraging at mobile flowers than at flowers that had been experimentally immobilized. In contrast, flower mobility imposed a cost on hummingbirds by significantly increasing their handling times and reducing their extraction rates relative to their interactions with immobile flowers. Field observations indicated that the motion observed during hummingbird visits did not occur when bees (Bombus spp., Apis mellifera) visited I. capensis flowers, which suggests that the mobility of I. capensis flowers is an adaptation for hummingbird pollination.

Joint infectious causation of human cancers.

Joint infectious causation of cancer has been accepted in a few well-studied instances, including Burkitt's lymphoma and liver cancer. In general, evidence for the involvement of parasitic agents in oncogenesis has expanded, and recent advances in the application of molecular techniques have revealed specific mechanisms by which host cells are transformed. Many parasites evolve to circumvent immune-mediated detection and destruction and to control critical aspects of host cell reproduction and survival: cell proliferation, apoptosis, adhesion, and immortalization. The host has evolved tight regulation of these cellular processes-the control of each represents a barrier to cancer. These barriers need to be compromised for oncogenesis to occur. The abrogation of a barrier is therefore referred to as an essential cause of cancer. Alternatively, some aspects of cellular regulation restrain but do not block oncogenesis. Relaxation of a restraint is therefore referred to as an exacerbating cause of cancer. In this chapter, we explore past and current evidence for joint infectious causation of cancer in the context of essential and exacerbating causes. We stress that discovery of joint infectious causation may provide great improvements in controlling cancer, particularly through the identification of many additional nonhuman targets for synergistic interventions for prevention and treatment.