Parasites live on or inside host organisms and rely on them for survival. To increase their chances of surviving and spreading, many parasites manipulate their hosts, changing characteristics such as how the host looks, behaves or reproduces. Abnormal tissues growths (known as tumors) can also manipulate their host to fulfil their own needs. For example, some tumors trigger growth of new blood vessels to increase their access to oxygen, nutrients, and to enable them to spread to other organs in a process known as metastasis. In rare cases, tumors can even spread between hosts, much like parasites.

The tiny freshwater animal Hydra oligactis can develop long-term tumors that are passed from one generation to the next. Intriguingly, hydras with these tumors grow more tentacles than those without, helping them to catch more food. This increases their ability to reproduce, which could potentially help to pass tumors on to other hydra hosts.

Boutry et al. aimed to explore whether long-term tumors are directly responsible for increasing the number of hydra tentacles and how they affect tumor transmission. To do so, the researchers tracked tentacle development in hydra with long-term tumors that are passed down over generations and those with spontaneous tumors, which are not transmissible. This revealed that hydras with long-term transmissible tumors develop significantly more tentacles than their healthy counterparts. Notably, hydras with spontaneously occurring tumors did not exhibit this trait.

Next, Boutry et al. transplanted tumor tissues from hydra with long-term tumors or spontaneous tumors onto healthy hydra. Only the long-term transmissible tumor tissue triggered additional tentacle development in previously healthy hosts. This suggests that the tumors have evolved the ability to manipulate host tissue development. Moreover, extra tentacles significantly improved feeding efficiency, leading to higher reproductive rates. Since hydra reproduce by producing genetically identical clones, a higher reproductive output translates into more opportunities for tumor cells to spread.

The findings of Boutry et al. provide the first evidence that transmissible tumors can actively reshape their host’s body structure to benefit their own transmission, suggesting they may have evolved sophisticated strategies to persist and proliferate. Future research could investigate the genetic and biochemical mechanisms underlying this ability. Understanding these processes may offer new insights into the evolutionary dynamics of tumors and identify any similarities with parasitism.

It is now widely established that animals (metazoans) are not autonomous entities, but rather holobionts composed of the host cell community, various commensal and mutualistic microorganisms, a diversity of parasitic taxa, and in many cases, tumor cells (Ujvari et al., 2016a; Dheilly et al., 2019). While it has been shown that parasites and mutualistic organisms have frequently evolved the ability to manipulate the host phenotype (e.g., reproduction, behavior, morphology, physiology, body odor; Hughes et al., 2012, Johnson and Foster, 2018; Naundrup et al., 2022) to favor their transmission and/or survival, sometimes inducing dramatic alterations (Doherty, 2020), this phenomenon has been poorly investigated in the context of host–tumor interactions. The only unambiguous evidence of such manipulation is found in the tumoral microenvironment when, for instance, malignant cells manipulate the surrounding healthy cells to induce the growth of blood vessels that bring oxygen and nutrients to the tumor, a process called neoangiogenesis (Hicklin and Ellis, 2005). Evidence regarding the ability of tumor cells to manipulate their host phenotype at other levels is scarce (see Tissot et al., 2016 for a review), and this probably reflects a real rarity of this phenomenon. Indeed, host manipulation capabilities often rely on sophisticated and complex adaptations that evolve during long coevolutionary processes, whereas tumors (neoplasms) most often evolve for only a few years and then die with their host without being able to transmit any acquired traits (Arnal et al., 2015). However, like ‘true parasites’, transmissible tumor cells (vertically – such as in Hydra oligactis [Domazet-Lošo et al., 2014; Boutry et al., 2022b]; or horizontally – such as in Tasmanian devils [Jones et al., 2008]) could more easily evolve manipulative abilities (Tissot et al., 2016; Ujvari et al., 2016b). Nevertheless, to date, we lack evidence that transmissible cancers can manipulate the phenotype of their hosts.

Hydra oligactis are cnidarians that frequently develop spontaneous tumors in the lab. These tumors correspond to abnormal proliferation of germline cells in the hydra’s ectoderm (Boutry et al., 2023). In 2014, Domazet-Lošo et al., 2014 described a fascinating case of two hydra lineages harboring neoplasms capable of vertical transmission through buds, during the asexual reproduction of hydras. Thanks to this transmission, these two tumorous hydra lines have been maintained under laboratory conditions for more than 15 years now (Lange, 2010). Beyond the presence of large tumor masses, a curious feature of these hydras is their increased number of tentacles. Specifically, while healthy polyps typically have 6–7 tentacles, tumorous polyps have between 8 and 13 tentacles, even up to 20 (Domazet-Lošo et al., 2014). This phenotype is particularly impressive given that tentacle numbers in hydras usually vary in a very small range (from 5 to 8 tentacles, depending on temperature and body size) (Shostak, 2012). Recently, Boutry et al., 2022a demonstrated that tumorous hydras featuring these supernumerary tentacles capture more prey than healthy ones, regardless of whether prey is rare or abundant in the environment. In contrast, wild specimens of H. oligactis developing spontaneous tumors when placed in laboratory conditions do not seem to develop additional tentacles (Domazet-Lošo et al., 2014). Since food intake, survival, as well as budding rate are usually positively correlated in hydras (Tökölyi et al., 2016), the presence of additional tentacles in certain tumorous hydras is likely to have an adaptive value, favoring host survival despite the cost of bearing tumors, and this can ultimately enhance the hydra’s reproductive potential and/or the tumor cells’ transmission (see also Boutry et al., 2022b).

However, whether the host or the tumor is responsible for the alteration of the tentacles number is not clear yet. Furthermore, in one H. oligactis lineage, called the St. Petersburg strain, tumor initiation and maintenance require the presence of a specific microbiome (Rathje et al., 2020), suggesting that bacteria may also be involved in the phenotypic alteration of the host to promote their own transmission. Here, through a series of experiments using a set of healthy and tumor tissue grafts (Figure 1) from tumors associated with different phenotypes, we attempted to determine whether the host or the tumor is responsible for the growth of additional tentacles in the tumorous hydra.

Figure 1

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Many parasites from different taxa (e.g., viruses, bacteria, protozoa, helminths, fungi, arthropods) have evolved the ability to manipulate the phenotype of their host to favor their own transmission and/or survival (Hughes et al., 2012). A wide variety of host traits can be modified by parasites, including reproduction, behavior, color, morphology, and/or physiology (Barnett, 1983; Dawkins, 1999; Agnew et al., 2000). Although theory predicts that transmissible cancers should evolve a true parasitic lifestyle over time (Dujon et al., 2020; Burioli et al., 2021), to date there has been no evidence of host phenotypic manipulation by transmissible tumor cell lines (Tissot et al., 2016).

In their pioneering work on transmissible tumors in hydra, Domazet-Lošo et al., 2014 mentioned the existence of an increased number of tentacles in the tumor-bearing lineages that have been propagated in the laboratory, but the precise cause of this phenotypic change was not understood. Here, we first highlight that this is not a general attribute of tumor-developing hydras since both Mt and SpB polyps developing spontaneous neoplasms do not show a similar large increase in the number of tentacles (Figure 2A). These results support the hypothesis that spontaneous tumors, which have no evolutionary history with their host, do not possess (or just to a small extent) the ability to influence its phenotype. Conversely, our results showed that transmissible tumors propagated in the laboratory for more than 10 years can induce the growth of additional tentacles even when they are transplanted in new hosts (even if this effect seems low with SpB grafted with tumors from Rob) as they seem to do in their original host lineage. In addition, while transplantation of spontaneous tumors never promoted an increase in tentacle numbers, transmissible tumors did, regardless of the origin of the recipient hydra (although one may suspect a different pattern between recipient strains that may not be detected due to a lack of power). These results are not consistent with the hypothesis that the development of additional tentacles could indicate a compensatory response of tumor-bearing polyps, for example, to better cope with resources redirected to growing tumors. Similarly, in agreement with previous work showing that the tumor phenotype can be observed in tumor-bearing hydras that do not consistently have an altered microbiome (this is the case for SpB, but not Rob; Domazet-Lošo et al., 2014), our transplantation experiments do not support the hypothesis that the alteration in tentacles’ number could be caused entirely by bacteria. Indeed, both the SpB and Rob tumors were able to trigger supernumerary tentacles in their new hosts, even if Rob microbiome is the same between tumorous and non-tumorous hydras (Domazet-Lošo et al., 2014). Thus, although the exact mechanisms promoting the growth of additional tentacles remain to be identified, this is the first evidence of transmissible tumor cells that have evolved the ability to manipulate an external phenotypic trait in their host. Further experiments focusing on transcriptional and proteomic changes (Takahashi et al., 2005) will certainly improve our knowledge of these phenotypic manipulations.

While it seems clear that the growth of supernumerary tentacles is induced only by the presence of transmissible tumor cells, to argue for host manipulation in the strict sense (as observed in the case of manipulative parasites; see Ewald, 1980; Poulin, 2010) it is necessary to demonstrate that this phenotypic change is indeed associated with an increase in tumor transmission. One possibility is that the supernumerary growth of tentacles, by increasing the rate of prey capture, merely compensates for the pathological costs associated with the presence of the tumor, the growth of which requires additional resources. Under this hypothesis, tumorous hydra with supernumerary tentacles would not necessarily exhibit an increased budding rate as it would be more indicative of a host manipulation aimed at better tolerating the tumor (i.e., compensating for vital resources diverted toward the tumor; Thomas et al., 2020). It is also possible than the growth of supernumerary tentacles, through a higher feeding rate, enhances the host’s budding rate and, consequently, the vertical transmission of the tumor. Our results support the hypothesis that tumors do indeed impose a cost on the reproductive potential of the host in terms of the weaker budding of tumoral individuals, but that this cost can be offset by the growth of supernumerary tentacles. Beyond this first conclusion, our data also support the hypothesis that the supernumerary growth of tentacles can sometimes not only compensate for the cost of the tumor, but also leads for some cancerous individuals to a significant increase in the number of buds, beyond the values presented by healthy individuals with a normal number of tentacles. Given that the transmission rate of tumors remains constant regardless of the budding rate (Boutry et al., 2022b), all our results thus suggest that tumor-induced supernumerary tentacle growth has likely evolved as an adaptation that enhances their transmission. Further research should focus on underlying the bio-physiological pathways and energetical costs of this manipulated phenotype (Takahashi et al., 2005; Sebens et al., 2017).

An intriguing finding from the present study is that in H. oligactis new tumors can develop following injury and/or transplantation of healthy tissue alone. Additional experiments are required to formally describe these outgrowths as tumors (although there are strong phenotypic similarities with spontaneous tumors; see Domazet-Lošo et al., 2014) and to understand the cause and mechanisms underlying their development. We can speculate that the act of grafting is likely to weaken the hydra’s ability to control abnormal cell proliferation and/or make them more susceptible to dysbiosis known to promote tumorigenesis (Rathje et al., 2020). In any case, despite the appearance of spontaneous tumors even after transplantation of healthy tissue, it is striking that only transmissible tumors are able to consistently alter and increase the number of tentacles in the transplanted individuals, which ultimately reinforces our conclusions.

An alternative explanation for our results would be that the increase in tentacle number following transplantation is a response of the hydra when non-self-tissues are introduced into the polyps. This would imply that the tumors, owing to their own evolution over years of vertical transmission, have diverged so significantly that they are perceived as non-self by the recipient hydras. However, we do not favor this hypothesis since when Hydra vulgaris are grafted with tissue from H. oligactis, we simply observe a destruction of the non-self-tissue (Bosch and David, 1986). In contrast, there is evidence of a lack of intra-specific non-self-recognition in H. vulgaris (Kuznetsov and Bosch, 2003), without any reporting of growth of additional tentacles. Also, since healthy and spontaneously tumorous hydras have been shown to sometimes grow a few additional tentacles, it would be necessary to explore in the future the extent to which the responsible environmental factors are similar to those potentially produced/exploited by transmissible tumors (see, for instance, Lefèvre et al., 2008). Further work, including experimental evolution, would be needed to assess the extent to which tentacle growth promotion is a capability that could be acquired over time from spontaneous tumor cells at least for those that also acquired the capacity to be transmitted.

This repository contains complete dataset, details of the performed analysis and supplementary analysis at https://justineboutry.github.io/Supplementary.io/.

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Author details

1. Justine Boutry

   CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   justine.boutry@ird.fr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0707-1202

2. Océane Rieu

   CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

   Contribution

   Investigation, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0001-2341-9993

3. Lena Guimard

   CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

   Contribution

   Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Jordan Meliani

   CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

5. Aurora M Nedelcu

   Department of Biology, University of New Brunswick, Fredericton, Canada

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7517-2419

6. Sophie Tissot

   CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

7. Nikita Stepanskyy

   CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

8. Beata Ujvari

   1. CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France
   2. School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Australia

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2391-2988

9. Rodrigo Hamede

   School of Biological Sciences, University of Tasmania, Hobart, Australia

   Contribution

   Conceptualization, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

10. Antoine M Dujon

    1. CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France
    2. School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Australia

    Contribution

    Formal analysis, Supervision, Validation, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1579-9156

11. Jácint Tökölyi

    MTA-DE “Momentum” Ecology, Evolution and Developmental Biology Research Group, Department of Evolutionary Zoology, University of Debrecen, Debrecen, Hungary

    Contribution

    Conceptualization, Supervision, Validation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6908-6493

12. Fréderic Thomas

    CREEC/CANECEV (CREES), MIVEGEC, Unité Mixte de Recherches, IRD 224-CNRS 5290 Université de Montpellier, Montpellier, France

    Contribution

    Conceptualization, Supervision, Funding acquisition, Validation, Writing – original draft, Project administration, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-2238-1978