Content uploaded by Gerald S Wilkinson
Author content
All content in this area was uploaded by Gerald S Wilkinson on Jun 08, 2015
Content may be subject to copyright.
A preview of the PDF is not available
Cancer susceptibility and reproductive trade-offs: A model of the evolution of cancer defences
Abstract and Figures
The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Trade-offs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction.
Figures - uploaded by Gerald S Wilkinson
Author content
All figure content in this area was uploaded by Gerald S Wilkinson
Content may be subject to copyright.
... Our results show that cancer adaptations can lag behind the body size change in birds under some scenarios. This may result in a longer lifespan and a lower cancer risk, but could also reduce the reproductive success (assuming trade-offs exist between these life history components, i.e. cancer defences are costly; Boddy et al., 2015). On the other hand, innovations that lengthen the average lifespan can select for higher cancer suppression, thereby lowering the effect of these evolutionary lags. ...
... We define the relationship between cancer defence and lifespan following the derivation of Kokko and Hochberg (2015). We follow Boddy et al. (2015) in assuming that cancer defences represent a shift towards a slower life history: strong defence yields a (probabilistically) longer lifespan but at a cost of reproductive success per unit time while the organism was alive (implemented as described in Methods section Deriving the selection coefficient of a mutation). We assume extrinsic mortality rate scales with body size following the allometric relationships from the literature (McCarthy et al., 2008), and also implement flight as an innovation that can reduce the extrinsic mortality rate in a variant of our model (as detailed in Methods sections Life history assumptions and Modelling body size change and flight, respectively). ...
... To compute lifespan for any level d, we first follow Boddy et al. (2015) and calculate the probability that an individual with N cells, alive at time t, has cancer by the time it has lived for t units of time, as: ...
An increased appreciation of the ubiquity of cancer risk across the tree of life means we also need to understand the more robust cancer defences some species seem to have. Peto’s paradox, the finding that large-bodied species do not suffer from more cancer even if their lives require far more cell divisions than those of small species, can be explained if large size selects for better cancer defences. Since birds live longer than non-flying mammals of an equivalent body size, and birds are descendants of moderate-sized dinosaurs, we ask whether ancestral cancer defence innovations are retained if body size shrinks in an evolutionary lineage. Our model derives selection coefficients and fixation events for gains and losses of cancer defence innovations over macroevolutionary time, based on known relationships between body size, intrinsic cancer risk, extrinsic mortality (modulated by flight ability) and effective population size. We show that evolutionary lags can, under certain assumptions, explain why birds, descendants of relatively large bodied dinosaurs, retain low cancer risk. Counterintuitively, it is possible for a bird to be ‘too robust’ for its own good: excessive cancer suppression can take away from reproductive success. On the other hand, an evolutionary history of good cancer defences may also enable birds to reap the lifespan-increasing benefits of other innovations such as flight.
... Owing to its complex, varied, and multifactorial nature, prevention involves focusing on factors driving specific cancers as well as consideration of more broad factors, such as viral infections, diet, and lifestyle (Lampe, 2020), that generally increase vulnerability to cancer. To inform this wider perspective, concepts from evolutionary biology are increasingly being applied to develop novel prevention and treatment strategies (Aktipis and Nesse, 2013;Boddy et al., 2015;Schooling, 2017). Evolutionary biology suggests reproductive success may take precedence over health and longevity (Wells et al., 2017). ...
... During cell metabolism, reactive oxygen species are generated as a toxic by-product (Ruggiero et al., 2008;Maciak and Michalak, 2015), which activates mutational process when in excess. More active metabolism per se increases the rate of genetic mutations (Maciak and Michalak, 2015) and the chance of tumor formation (Boddy et al., 2015). Cancer risk may increase when these overwhelming mutational events cannot be hedged by somatic maintenance such as DNA repair (Aktipis and Nesse, 2013;Boddy et al., 2015;Maciak and Michalak, 2015) and tissue repair (Aktipis and Nesse, 2013). ...
... More active metabolism per se increases the rate of genetic mutations (Maciak and Michalak, 2015) and the chance of tumor formation (Boddy et al., 2015). Cancer risk may increase when these overwhelming mutational events cannot be hedged by somatic maintenance such as DNA repair (Aktipis and Nesse, 2013;Boddy et al., 2015;Maciak and Michalak, 2015) and tissue repair (Aktipis and Nesse, 2013). Higher BMR may also compromise immunity (Maciak and Michalak, 2015), which has also been suggested to link with higher cancer risk (Aktipis and Nesse, 2013;Boddy et al., 2015;Maciak and Michalak, 2015). ...
Background: Basal metabolic rate is associated with cancer, but these observations are open to confounding. Limited evidence from Mendelian randomization studies exists, with inconclusive results. Moreover, whether basal metabolic rate has a similar role in cancer for men and women independent of insulin-like growth factor 1 increasing cancer risk has not been investigated.
Methods: We conducted a two-sample Mendelian randomization study using summary data from the UK Biobank to estimate the causal effect of basal metabolic rate on cancer. Overall and sex-specific analysis and multiple sensitivity analyses were performed including multivariable Mendelian randomization to control for insulin-like growth factor 1.
Results: We obtained 782 genetic variants strongly ( p -value < 5 × 10 –8 ) and independently ( r ² < 0.01) predicting basal metabolic rate. Genetically predicted higher basal metabolic rate was associated with an increase in cancer risk overall (odds ratio, 1.06; 95% confidence interval, 1.02–1.10) with similar estimates by sex (odds ratio for men, 1.07; 95% confidence interval, 1.002–1.14; odds ratio for women, 1.06; 95% confidence interval, 0.995–1.12). Sensitivity analyses including adjustment for insulin-like growth factor 1 showed directionally consistent results.
Conclusion: Higher basal metabolic rate might increase cancer risk. Basal metabolic rate as a potential modifiable target of cancer prevention warrants further study.
... As mentioned before, antagonistic pleiotropy is when one gene has opposite effects on fitness at different ages, such that their effects are beneficial in early life, when natural selection is strong, but harmful at later ages, when selection weakens. In a theoretical study, Boddy et al. (2015) investigated the possible links between cancer risks and the level of intraspecific competition, assuming that an underlying resource-based tradeoff between competitiveness and allocation into cancer defenses exists. As has been empirically observed (see Clocchiatti et al., 2016 for an example in humans), the model first showed that cancer prevalence is expected to be lower in females than in males, since mating competition usually has greater reproductive payoffs for males than for females (Clutton-Brock and Vincent, 1991) and also because of the immune-enhancing effect of estrogen (Taneja, 2018; even if the picture is more variable in humans, Mulder and Ross, 2019). ...
... These two processes, reproductive aging and oncogenic processes, can share similar proximate origins. As emphasized in the sections above, an elevated reproductive expenditure could be responsible for an increased risk of cancer (Boddy et al., 2015). Interestingly, there is compelling evidence that such substantial allocation to reproduction during early-life is also detrimental in terms of an earlier/stronger reproductive aging (e.g., Nussey et al., 2006 andLemaître et al., 2014, for examples in females and males red deer, Cervus elaphus, respectively) and the physiological pathways that have been suggested to mediate the link between early-and late-life reproductive performance are strikingly similar to the one suggested to be involved in the reproductive effort-cancer trade-offs (e.g., oxidative stress, telomere attrition, see Kalmbach et al., 2015). ...
Reproduction is one of the most energetically demanding life-history stages. As a result, breeding individuals often experience trade-offs, where energy is diverted away from maintenance (cell repair, immune function) toward reproduction. While it is increasingly acknowledged that oncogenic processes are omnipresent, evolving and opportunistic entities in the bodies of metazoans, the associations among reproductive activities, energy expenditure, and the dynamics of malignant cells have rarely been studied. Here, we review the diverse ways in which age-specific reproductive performance (e.g., reproductive aging patterns) and cancer risks throughout the life course may be linked via trade-offs or other mechanisms, as well as discuss situations where trade-offs may not exist. We argue that the interactions between host-oncogenic processes should play a significant role in life-history theory, and suggest some avenues for future research.
... Moreover, once mature, the adult size needs to be maintained, balancing the cell turnover that occurs throughout life (Fuchs & Steller, 2011;Galluzzi et al., 2018); again, larger organisms maintain a larger cell population. Mature body size is also not the only axis of variation that is likely to matter for the optimal strategy: extrinsic mortality can also matter (Boddy, Kokko, Breden, Wilkinson, & Aktipis, 2015). Organisms that face a high risk of extrinsic mortality need to ensure that they mature fast enough to reproduce before they die, and their shorter lives can diminish the importance of cancer suppression (Kokko & Hochberg, 2015). ...
... Fitness maintenance is easy if the novel body size is small (to the left of the vertical lines in c, d) but hard if large (to the right of the vertical lines in b, c), with the precise shape of the latter pattern being strategy-dependent. All parameters not given in the figure are as in Figure 2 that the remaining challenges relate to extrinsic mortality only (we here follow a modelling tradition of calling age-independent mortalities that the organism cannot change as "extrinsic"; Abrams, 1993;Boddy et al., 2015;Carnes & Olshansky, 1997). These could potentially explain the variation in telomere length or telomerase expression in mammals, especially in smaller ones (Gomes et al., 2011). ...
Multicellularity evolved independently in multiple lineages, yielding organisms with a wide range of adult sizes. Building an intact soma is not a trivial task, when dividing cells accumulate damage. Here, we study “ontogenetic management strategies,” that is rules of dividing, differentiating and killing somatic cells, to examine two questions: first, do these rules evolve differently for organisms differing in the target mature body size, and second, how well a strategy evolved in small-bodied organisms performs if implemented in a large body—and vice versa (“large”-evolved strategies in small bodies). We model the growth and mature lifespan of an organism starting from a single cell and optimize, using a genetic algorithm, trait combinations across a range of target sizes, with seven evolving traits: (a) probability of asymmetric division, (b) probability of differentiation (per symmetric cell division), (c) Hayflick limit, (d) damage response threshold, (e) damage response strength, (f) number of differentiation steps and (g) division propensity of cells relative to “stemness.” Some but not all traits evolve differently depending on body size: large-bodied organisms perform best with a smaller probability of differentiation, a larger number of differentiation steps on the way to form a tissue and a higher threshold of cellular damage to trigger cell death, than small organisms. Strategies evolved in large organisms are more robust: they maintain high performance across a wide range of body sizes, while those that evolved in smaller organisms fail when attempting to create a large body. This highlights an asymmetry: under various risks of developmental failure and cancer, it is easier for a lineage to become miniaturized (should selection otherwise favour this) than to increase in size.
... Many of the life history responses observed in the context of hostparasite interactions have been proposed to be also relevant in the context of cancer. The theory that cancer is a parasitic disease has a long history (Park 1899;Plimmer 1903;Crespi & Summers 2006;Boddy et al. 2015;Ujvary et al. 2016). Despite important differences between infectious diseases and cancers, the impact of tumor development can be closely compared to that of infections by foreign organisms, as neoplasia (i.e., new uncontrolled growth of cells that is not under physiologic control) broadly mimics the health-as well as the fitness-consequences of infections (Vittecoq et al. 2015). ...
... Peto's paradox is not a paradox from a life history perspective. Based on life history theory we expect a Bowhead whale that lives over 200 years to do a better job at maintaining its soma than a field mouse with a lifespan of less than 4 years [52,53]. Slow-life history animals, such as whales and elephants, have strong selective pressure to maintain their genome-leading to better DNA repair and immune function, which can all contribute to lower cancer risk. ...
Sir Richard Peto is well known for proposing puzzling paradoxes in cancer biology—some more well-known than others. In a 1984 piece, Peto proposed that after decades of molecular biology in cancer research, we are still ignorant of the biology underpinning cancer. Cancer is a product of somatic mutations. How do these mutations arise and what are the mechanisms? As an epidemiologist, Peto asked if we really need to understand mechanisms in order to prevent cancer? Four decades after Peto’s proposed ignorance in cancer research, we can simply ask, are we still ignorant? Did the great pursuit to uncover mechanisms of cancer eclipse our understanding of causes and preventions? Or can we get closer to treating and preventing cancer by understanding the underlying mechanisms that make us most vulnerable to this disease?
... This includes one sex choosing which individuals of the other sex to mate with (inter-sexual competition) as well as members of one sex competing with each other for mating opportunities (intra-sexual competition). If there is a lot of reproductive skew, if a minority of individuals in a population get all the mating opportunities, then competition to be in that reproductive minority can be intense, and selection for traits that provide for success in such competition can swamp other selective pressures [like cancer suppression (Boddy et al. 2015)]. ...
Abstract Does asking students to apply concepts from evolution to a fictional context, compared to a novel biological context, improve their understanding, exam performance or enjoyment of the material? Or does it harm their education by taking time away from true biology? At our institution, we sometimes ask students to apply life history theory to species from fictional movies, television shows or books. Previously, we had used a factual article on life history theory, to supplement our textbook. We wrote an alternative introduction to life history theory (included in the additional files for educational use), using Tolkien’s fictional species from his Lord of the Rings books. We also introduce the biological species definition, sexual selection, sexual dimorphism, kin selection, and the handicap principle, as those concepts arose naturally in the discussion of the fictional species. Life history theory predicts strong correlations between traits affecting reproduction, growth and survival, which are all shaped by the ecology of the species. Thus, we can teach life history theory by asking students to infer traits and aspects of the ecology of a fictional species that have never been described, based on the partial information included in the fictional sources. In a large, third year undergraduate evolution course at Arizona State University, we randomized 16 tutorial sections of a total of 264 students to either read our article on the life history theory of Lord of the Rings, or the factual article we had used previously in the course. We found that the exam performance on life history questions for the two groups were almost identical, except that fans of The Lord of the Rings who had read our article did better on the exam. Enjoyment, engagement and interest in life history theory was approximately a full point higher on a 5-point Likert scale for the students that had read the fictional article, and was highly statistically significantly different (T-test p
Background:
Observational studies have demonstrated that basal metabolic rate (BMR) is associated with the risk of endometrial cancer (EC) and ovarian cancer (OC). However, it is unclear whether these associations reflect a causal relationship.
Objective:
To reveal the causality between BMR and EC and OC, we performed the first comprehensive two-sample Mendelian randomization (MR) analyses.
Methods:
Genetic variants were used as proxies of BMR. GWAS summary statistics of BMR, EC, and OC were obtained from the UK Biobank Consortium, Endometrial Cancer Association Consortium, and Ovarian Cancer Association Consortium, respectively. The inverse variance weighted method was employed as the main approach for MR analysis. A series of sensitivity analyses were implemented to validate the robustness and reliability of the results.
Results:
BMR was significantly related to an increased risk of EC (ORSD = 1.49; 95%CI: 1.29-1.72; p-Value < 0.001) and OC (ORSD = 1.21; 95%CI:1.08-1.35; p-Value < 0.001). Furthermore, the stratified analysis indicated that BMR was positively associated with endometrioid endometrial cancer (EEC) (ORSD = 1.45; 95%CI, 1.23-1.70; p-Value < 0.001), clear cell ovarian cancer(CCOC) (ORSD = 1.89; 95%CI:1.35-2.64; p-Value < 0.001) and endometrioid ovarian cancer risk (EOC) (ORSD = 1.45; 95%CI:1.12-1.88; p-Value = 0.005). However, there were no significant associations of BMR with invasive mucinous ovarian cancer (IMOC), high grade serous ovarian cancer (HGSOC), and low grade serous ovarian cancer (LGSOC). The robustness of the above results was further verified in sensitivity analyses.
Conclusion:
The MR study provided etiological evidence for the positive association of BMR with the risk of EC, EEC, OC, CCOC, and EOC. But this study did not provide enough evidence suggesting the causal associations of BMR with IMOC, HGSOC, and LGSOC.
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. 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 a multifaceted process. From research to date, it appears that the relationship between telomere length and cancer risk is likely non‐linear with good evidence that both (too) long and (too) short telomeres can be associated with an increased cancer risk. The ability and propensity of organisms to respond to the interplay of telomere dynamics and oncogenic processes, depends on a 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.
Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We review the existing literature on cancer and cancer-like phenomena across life, not only focusing on complex multicellularity but also reviewing cancer-like phenomena across the tree of life more broadly. We find that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Cheating on division of labour, exhibited by a lack of differentiation and disorganized cell masses, has been observed in all forms of multicellularity. This suggests that deregulation of differentiation is a fundamental and universal aspect of carcinogenesis that may be underappreciated in cancer biology. Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer.
© 2015 The Author(s) Published by the Royal Society. All rights reserved.
The GH/IGF-I axis has a clearly established role in somatic growth regulation and there is much evidence suggesting that it can play a contributing role in neoplastic tissue growth; a number of recent epidemiological reports indicate that it may also be an important determinant of cancer incidence. Whilst there have been previous reports of changes to the axis in patients with established cancers, these new studies are distinct in being prospective and the inferences that can be made from this are outlined in this review. The recent studies are considered within the context of other indirect epidemiological evidence, and together indicate that the GH/IGF-I axis may establish the level of predisposition to a number of common cancers and indeed that such risk may be programmed from early life. There is considerable evidence for a number of possible mechanisms, both direct and indirect, which could account for the associations between GH/IGF-I levels and cancer incidence; these mechanisms are briefly sum-marised. The implications of the new findings are then discussed in relation to the increasing clinical usage of chronic GH administration and the need for further studies to establish any consequent increase in cancer risk. Finally the opportunities for further work to optimise cancer risk assessment and risk reduction strategies are highlighted.
It has long been accepted that modern reproductive patterns are likely contributors to breast cancer susceptibility because
of their influence on hormones such as estrogen and the importance of these hormones in breast cancer. We conducted a meta-analysis
to assess whether this ‘evolutionary mismatch hypothesis’ can explain susceptibility to both estrogen receptor positive (ER-positive)
and estrogen receptor negative (ER-negative) cancer. Our meta-analysis includes a total of 33 studies and examines parity,
age of first birth and age of menarche broken down by estrogen receptor status. We found that modern reproductive patterns
are more closely linked to ER-positive than ER-negative breast cancer. Thus, the evolutionary mismatch hypothesis for breast
cancer can account for ER-positive breast cancer susceptibility but not ER-negative breast cancer.
Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (1971) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have a lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness.
