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.

The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

Identifying key questions in the ecology and evolution of cancer.

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.

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.

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.

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.

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.

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.

Infections and cancer: the "fifty shades of immunity" hypothesis.

BACKGROUND: Since the beginning of the twentieth century, infection has emerged as a fundamental aspect of cancer causation with a growing number of pathogens recognized as oncogenic. Meanwhile, oncolytic viruses have also attracted considerable interest as possible agents of tumor destruction. DISCUSSION: Lost in the dichotomy between oncogenic and oncolytic agents, the indirect influence of infectious organisms on carcinogenesis has been largely unexplored. We describe the various ways - from functional aspects to evolutionary considerations such as modernity mismatches - by which infectious organisms could interfere with oncogenic processes through immunity. Finally, we discuss how acknowledging these interactions might impact public health approaches and suggest new guidelines for therapeutic and preventive strategies both at individual and population levels. Infectious organisms, that are not oncogenic neither oncolytic, may play a significant role in carcinogenesis, suggesting the need to increase our knowledge about immune interactions between infections and cancer.

Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research.

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.

Cancer: an emergent property of disturbed resource-rich environments? Ecology meets personalized medicine.

For an increasing number of biologists, cancer is viewed as a dynamic system governed by evolutionary and ecological principles. Throughout most of human history, cancer was an uncommon cause of death and it is generally accepted that common components of modern culture, including increased physiological stresses and caloric intake, favor cancer development. However, the precise mechanisms for this linkage are not well understood. Here, we examine the roles of ecological and physiological disturbances and resource availability on the emergence of cancer in multicellular organisms. We argue that proliferation of 'profiteering phenotypes' is often an emergent property of disturbed, resource-rich environments at all scales of biological organization. We review the evidence for this phenomenon, explore it within the context of malignancy, and discuss how this ecological framework may offer a theoretical background for novel strategies of cancer prevention. This work provides a compelling argument that the traditional separation between medicine and evolutionary ecology remains a fundamental limitation that needs to be overcome if complex processes, such as oncogenesis, are to be completely understood.

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.

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.

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.

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.

Toward a general evolutionary theory of oncogenesis.

We propose an evolutionary framework, the barrier theory of cancer, which is based on the distinction between barriers to oncogenesis and restraints. Barriers are defined as mechanisms that prevent oncogenesis. Restraints, which are more numerous, inhibit but do not prevent oncogenesis. Processes that compromise barriers are essential causes of cancer; those that interfere with restraints are exacerbating causes. The barrier theory is built upon the three evolutionary processes involved in oncogenesis: natural selection acting on multicellular organisms to mold barriers and restraints, natural selection acting on infectious organisms to abrogate these protective mechanisms, and oncogenic selection which is responsible for the evolution of normal cells into cancerous cells. The barrier theory is presented as a first step toward the development of a general evolutionary theory of cancer. Its attributes and implications for intervention are compared with those of other major conceptual frameworks for understanding cancer: the clonal diversification model, the stem cell theory and the hallmarks of cancer. The barrier theory emphasizes the practical value of distinguishing between essential and exacerbating causes. It also stresses the importance of determining the scope of infectious causation of cancer, because individual pathogens can be responsible for multiple essential causes in infected cells.

Infection, mutation, and cancer evolution.

An understanding of oncogenesis can be fostered by an integration of mechanistic studies with evolutionary considerations, which help explain why these mechanisms occur. This integration emphasizes infections and mutations as joint essential causes for many cancers. It suggests that infections may play a broader causal role in oncogenesis than has been generally appreciated. An evolutionary perspective also suggests that oncogenic viruses will tend to be transmitted by routes that provide infrequent opportunities for transmission, such as transmission by sexual and salivary contact. Such routes increase the intensity of natural selection for persistence within hosts, and molecular mechanisms for persistence often compromise critical barriers to oncogenesis, particularly cell cycle arrest, apoptosis, and a cap on the total number of divisions that a cell can undergo.