Infection and cancer in multicellular organisms

Importantly, cancer cells not only act similarly to parasites by diverting energy and resources from other vital functions of the host, but also a substantial proportion of malignancies are caused by infections (ca. 20% of human cancers; Ewald and Swain Ewald, Reference Ewald and Swain Ewald2015). Thus, infections could contribute to cancer directly or indirectly. Direct initiation results from pathogens (particularly intracellular parasites) altering cellular regulatory mechanisms (e.g. apoptosis and cell-cycle arrest) and cell proliferation rates, and therefore breaking down cellular barriers that would otherwise prevent oncogenesis. Infection-induced inflammatory responses may also result in increased mutation rates and compromised proliferation signals, and concomitantly indirectly initiate malignant transformations (reviewed in Ewald and Swain Ewald, Reference Ewald and Swain Ewald2012, Reference Ewald and Swain Ewald2013). Although protozoans (e.g. Plasmodium falciparum, Molyneux et al. Reference Molyneux, Rochford, Griffin, Newton, Jackson, Menon, Harrison, Israels and Bailey2012), bacteria (e.g. Helicobacter pylori, Mager Reference Mager2006; Ewald and Swain Ewald, Reference Ewald and Swain Ewald2014) and trematodes (e.g. Schistosoma haemotobium, Mostafa et al. Reference Mostafa, Sheweita and O'Connor1999; Ewald and Swain Ewald, Reference Ewald and Swain Ewald2014) have all been shown to directly or indirectly cause malignancies, viruses are the most frequent sources of infection-induced cancers (reviewed by Ewald and Swain Ewald, Reference Ewald and Swain Ewald2015). While oncogenic pathogens and their induced malignancies are well documented in humans and domestic animals, they are less well recorded in undomesticated captive animals, and are largely undetected in nature. Ewald and Swain Ewald (Reference Ewald and Swain Ewald2015) have proposed several explanations for why cancer is rarely found in natural populations: (1) although benign neoplasms occur pervasively in multicellular organisms they rarely transition to detectable malignant tumours; (2) reduced survival due to malignancy [as a direct (detrimental to health) or indirect (increased predation) consequence of cancer] hinders detectability; and (3) diagnostics and evaluation of malignancy are inconsistent across species. The full scope of infection-induced cancers is still not known for any multicellular species, but interestingly infection-induced cancers are known to occur at young ages (e.g. cervical cancer in humans).

Cancer, being induced by pathogens or acting analogously to parasites, or both, clearly has a major impact on host’ LH traits. We next discuss cancer as selective force on host LH traits.

Why should cancer influence LH traits?

Cancer, both solid tumours and blood cancers, can be thought of as a developing species that behaves in a manner akin to parasites (Duesberg et al. Reference Duesberg, Mandrioli, McCormack and Nicholson2011). As far as host LH traits are concerned, parasites likely play an important role in their evolution because they often impose important selective pressures on the host (Michalakis and Hochberg, Reference Michalakis and Hochberg1994). Similarly, cancer cells depend on their hosts for sustenance, proliferating inside their bodies, exploiting them for energy and resources, and thereby impairing their health and fitness. Based on these similarities, it is predicted that several of the responses that have evolved in the context of host–parasite interactions should also be relevant in the context of cancer (Vittecoq et al. Reference Vittecoq, Roche, Daoust, Ducasse, Missé, Abadie, Labrut, Renaud, Gauthier-Clerc and Thomas2013). Evolutionary theory on host–parasite interactions postulates that host species should also be under selective pressures to avoid the source of the pathology in the first instance (e.g. Hart, Reference Hart1994), then prevent its progression once infected, and finally alleviate the fitness costs if further development is not preventable (Thomas et al. Reference Thomas, Guégan and Renaud2009).

Costs on LH traits

Parasitic organisms exploit their host for resources that could otherwise be used for maintenance, growth and/or reproduction (Poulin, Reference Poulin2007; Schmid-Hempel, Reference Schmid-Hempel2011). Direct costs resulting from this exploitation can cause inter-individual (or inter-population) variation in LH traits such as fecundity and survival (Thomas et al. Reference Thomas, Guégan, Michalakis and Renaud2000). At the same time, inter-individual differences in physiology and LH productivity may ‘drive’ or encourage consistent variation in behaviour (Biro and Stamps, Reference Biro and Stamps2008; Biro et al. Reference Biro, Adriaenssens and Sampson2014), and differences in behaviour can in turn affect the likelihood of encounter rates with parasites and transmission of them between one another (Boyer et al. Reference Boyer, Réale, Marmet, Pisanu and Chapuis2010; Dunn et al. Reference Dunn, Cole and Quinn2011; Bull et al. Reference Bull, Godfrey and Gordon2012; Seaman and Briffa, Reference Seaman and Briffa2015). Thus, inter-individual (or inter-population) variation in LH traits could at the same time be both causes and consequences of parasitism. Additionally, direct modifications of the host's LH traits may also result from toxic products of the parasite's metabolism (Michalakis, Reference Michalakis, Thomas and Guégan2009). Finally, the complex machinery constituting the immune system often incurs metabolic costs that indirectly generate modifications of the host's LH traits as a result of trade-offs (Sorci et al. Reference Sorci, Boulinier, Gauthier-Clerc, Faivre, Thomas, Guégan and Renaud2009). The extent to which these trade-offs are manifest are likely to differ among individuals that differ in their energetic and productive capacities (van Noordwijk and de Jong, Reference van Noordwijk and de Jong1986; Reznick et al. Reference Reznick, Nunney and Tessier2000; Biro and Stamps, Reference Biro and Stamps2008).

In the context of malignancies, the time elapsing from the appearance of the first cancerous cells to the development of a metastatic cancer may vary from weeks to years, or even decades, depending on individuals and types of cancer. The shape of the relationship between health/fitness-related traits and tumour development is not precisely known for most species and most cancers (see Vittecoq et al. Reference Vittecoq, Ducasse, Arnal, Møller, Ujvari, Jacqueline, Tissot, Missé, Bernex, Pirot, Lemberger, Abadie, Labrut, Bonhomme, Renaud, Roche and Thomas2015). Nonetheless, individuals harbouring tumours are likely to be, sooner or later, in a worse condition than healthy individuals on average, even if individuals differ in their intrinsic energetic and LH capacities. Frequent symptoms of cancer are extreme tiredness (fatigue) or weight loss, resulting from cancer cells using up much of the body's energy supply, or releasing substances that modify the way the body derives energy from food (Wagner and Cella, Reference Wagner and Cella2004; Ryan et al. Reference Ryan, Carroll, Ryan, Mustian, Fiscella and Morrow2007). Although cancer-related fatigue is one of the most prevalent symptoms in cancer sufferers, the precise aetiology of this distressing and debilitating symptom remains poorly understood. Given that energy allocation relative to energy acquisition is at the heart of predictions for how competing LH traits might be affected by such energy ‘drains’ (van Noordwijk and de Jong, Reference van Noordwijk and de Jong1986), a research focus on energetics might thus be very informative for understanding LH responses to cancer.

Plastic adjustments of LH traits

Host LH traits can undergo flexible and adaptive responses to parasitism in order to compensate for the negative costs exerted by parasites on host fitness (Hochberg et al. Reference Hochberg, Michalakis and de Meeus1992; Michalakis and Hochberg, Reference Michalakis and Hochberg1994). For instance, hosts unable to resist infection by other means (e.g. immunological resistance, inducible defences or long-distance migration) are theoretically favoured by selection if they partly compensate the parasite-induced losses by reproducing earlier (Forbes, Reference Forbes1993) or if their behaviour impedes the transmission of the parasite in spatially structured contexts (Débarre et al. Reference Débarre, Lion, van Baalen and Gandon2012). Infected individuals may, for instance, increase their reproductive activities before dying or being castrated by parasites (Minchella and Loverde, Reference Minchella and Loverde1981; Sorci et al. Reference Sorci, Clobert and Michalakis1996; Polak and Starmer, Reference Polak and Starmer1998; Adamo, Reference Adamo1999), or simply increase their fitness through kin selection-mediated effects (Débarre et al. Reference Débarre, Lion, van Baalen and Gandon2012; Iritani and Iwasa, Reference Iritani and Iwasa2014). Among recent examples, Vézilier et al. Reference Vézilier, Nicot, Gandon and Rivero2015 demonstrated that female mosquitoes parasitized by P. falciparum begin laying their eggs two days earlier, thereby compensating the loss of fecundity due to their reduced lifespan. In the context of cancer, preliminary results (Arnal et al. unpublished data) suggest that females in Drosophila harbouring early stages of tumours tend to reach the peak of oviposition earlier than healthy females before concomitantly dying sooner. As compelling as these recent studies are, clearly additional studies of this kind are necessary before generalizations can be made.

Parental ‘programming’ and inheritance of LH traits

The influence of parental (non-genetic) effects on their offspring's phenotype is increasingly acknowledged as an important adaptive mechanism in animals (Mousseau et al. Reference Mousseau, Uller, Wapstra and Badyaev2009; Wolf and Wade, Reference Wolf and Wade2009). There is a growing body of evidence indicating that parasitic exploitation of a host can lead to changes in the phenotype of the hosts’ offspring, though the latter are not parasitized (reviewed by Poulin and Thomas, Reference Poulin and Thomas2008). For instance, animals infected with harmful parasites often produce smaller offspring because parents cannot allocate sufficient energy to reproduction (e.g. Hakkarainen et al. Reference Hakkarainen, Huhta, Koskela, Mappes, Soveri and Suorsa2007; Gallizzi et al. Reference Gallizzi, Alloitteau, Harrang and Richner2008). Additionally, paternal stress can affect offspring phenotype by altering sperm phenotype and affecting post-zygotic development and performance (Crean et al. Reference Crean, Dwyer and Marshall2012, Reference Crean, Dwyer and Marshall2013; Rando, Reference Rando2012; Bromfield et al. Reference Bromfield, Schjenken, Chin, Care, Jasper and Robertson2014; Zajitschek et al. Reference Zajitschek, Hotzy, Zajitschek and Immler2014). Several proximate mechanisms have been put forward to explain parental effects due to infections, most involving hormonal or other physiological pathways, as well as epigenetic phenomena, and ultimately leading to offspring that are pre-adapted to the parasites they are most likely to encounter based on their parent's experience (Sorci and Clobert, Reference Sorci and Clobert1995).

Are there consequences of having ‘cancerous’ parents? Given that most if not all individuals among metazoan species accumulate precancerous lesions and in situ tumours in many organs as they age (Folkman and Kalluri, Reference Folkman and Kalluri2004), this question is relevant to virtually all multicellular organisms. Few cancers are directly transmissible, so the risk of offspring contagion is often not applicable. However, because of the health consequences associated with tumourigenesis, parents with more or less advanced malignancies are likely to be affected in their ability to provide adequate resources/parental care to their offspring. To our knowledge this question has never been empirically addressed. As for parasites, deeper trans-generational effects probably exist, as suggested by several studies indicating that epigenetic modifications that influence cancer risk can be inherited through the germline across multiple generations (reviewed in Fleming et al. Reference Fleming, Huang and Toland2008). Similar to infections, cancer risk could be correlated within families across generations. This should presumably be the case in species with low dispersal, living in areas (naturally or artificially) contaminated by mutagenic substances, because both parents and offspring experience the same ecological contexts. Similarly, the same should apply to cancer caused by inherited oncogenic vulnerabilities. At the moment there is little evidence available on the consequences of having parents harbouring tumours and/or oncogenic mutations on offspring phenotype, in terms of costs and adaptive (non-genetic) transgenerational effects.

Although parent-to-offspring transmission of cancer cells may be uncommon, parent-to-offspring transmission of infections that induce cancer appear to be moderately common (Ewald and Swain Ewald, Reference Ewald and Swain Ewald2015). For example, in humans, T-lymphotropic virus type 1 (Coovadia et al. Reference Coovadia, Rollins, Bland, Little, Coutsdoudis, Bennish and Newell2007) and potentially hepatitis B virus are transmissible to offspring in milk (but see Chen et al. Reference Chen, Chen, Wen, Xu, Zhang, Zhou and Hu2013) and cause cancer in a substantial proportion of those offspring (Ewald and Swain Ewald, Reference Ewald and Swain Ewald2015). In captive wildlife, vertical transmission of simian T-lymphotropic viruses in apes (Parrish et al. Reference Parrish, Brown, Chanbancherd, Gettayacamin and Parrish2004; d'Offay et al. Reference d'Offay, Eberle, Sucol, Schoelkopf, White, Valentine, White and Lerche2007), feline immunodeficiency virus in cats (O'Neil et al. Reference O'Neil, Burkhard, Diehl and Hoover1995) and mouse mammary tumour virus in mice (Bentvelzen et al. Reference Bentvelzen, Daams, Hageman and Calafat1970) is known, but their occurrence in the wild requires further study.

Evolutionary change in the host population

Whenever there is a genetic basis to LH traits, or trade-offs between them, evolutionary change in the host population can occur in response to ‘infection’ by cancer just as it would with parasites. For instance, selection may favour early sexual maturity when the risk of future infection and mortality is high. Indeed, snails from localities with a high prevalence of castrating trematodes become sexually mature earlier than conspecifics living in areas of low prevalence (Lafferty, Reference Lafferty1993; Fredensborg and Poulin, Reference Fredensborg and Poulin2006). One of the best examples of altered LH strategies in response to exposure to cancer involves the Tasmanian devils (Sarcophilus harrisii) and their transmissible cancer, the devil facial tumour disease (DFTD). Following the appearance of DFTD, devils have responded to the cancer-induced mortality by rapidly transitioning from a late maturing iteroparous (multiple reproductive cycles) to an early maturing semelparous (single breeding) reproductive strategy (Jones et al. Reference Jones, Cockburn, Hamede, Hawkins, Hesterman, Lachish, Mann, McCallum and Pemberton2008).

Concluding remarks

Is it justifiable to ignore LH traits when studying oncogenic phenomena? In the light of this discussion, we suggest that the answer is clearly no. Cancer can directly affect LH traits by imposing costs and/or indirectly by triggering plastic adjustments and evolutionary responses, just as parasites are well known to do. Reciprocally, these effects can potentially influence cancer risks, through the evolution of differential cancer vulnerabilities in populations (e.g. Kokko and Hochberg, Reference Kokko and Hochberg2015). For instance, BRCA1 and BRCA2 mutations are inherited and predispose women to breast and ovarian cancer, but even though carriers of these mutations have a reduced survival, they also have enhanced fertility (Easton et al. Reference Easton, Ford and Bishop1995; Smith et al. Reference Smith, Hanson, Mineau and Buys2012). This result may indicate antagonistic pleiotropy (i.e. when one gene controls more than one trait, at least one of these traits is beneficial to the organism's fitness and at least one is detrimental to fitness). However, since the adaptive response by the host also favours the transmission of BRCA1 and BRCA2 to the next generations, this suggests that the existence of LH trait adjustments could influence the persistence of oncogenic mutations in certain populations. In addition, such adjustments would be, in our opinion, a potentially more parsimonious alternative to the antagonistic pleiotropy hypothesis classically invoked to explain why oncogenic mutations persist at a higher frequency than expected by the mutation-selection balance (e.g. Bodmer, Reference Bodmer2006; Risch et al. Reference Risch, McLaughlin, Cole, Rosen, Bradley, Fan, Tang, Li, Zhang, Shaw and Narod2006).

To understand the evolution of LH traits in a cancer context, one must consider the complete ecological context in which individuals developing tumours live. Unfortunately, there is only limited data to date, supporting the hypotheses we have outlined above (Table 1). Clearly more data and research, including on the assumptions of cancers potentially affecting fitness related traits, are needed to draw a more substantiated parallel between cancer and infectious diseases. Because one single method or model cannot thoroughly integrate all the complexity of the processes we have discussed, researchers interested in these adaptive responses must engage in greater exchanges and collaborations involving scientists from different disciplines. Finally, we strongly encourage researchers to systematically explore the myriad of symptoms displayed by cancerous patients in order to discover those that could be LH trait responses, vs those that illustrate pathological costs without adaptive value.