Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Comment on ‘How the evolution of multicellularity set the stage for cancer’

We read the paper “How the evolution of multicellularity set the stage for cancer” with interest, which was published in a recent issue of the British Journal of Cancer.1 In this paper, the authors underlined that disruption of gene regulatory networks, which maintain the multicellular state, induces cancer. The atavistic model of cancer is undoubtedly effective in integrating many parameters in a performing heuristic framework. It hypothesises that cancer results from a transition from multicellularity to unicellularity, through an active constrained process. In this schema, dysregulation of a set of fundamental points of vulnerability, which govern multicellularity maintenance, is sufficient to model carcinogenesis.

First, an important clarification needs to be made about the cellular state of cancer cells. A tumour is a heterogeneous community of cancerous and non-cancerous cells whose global behaviour depends on numerous social-ecological and parasitic interactions. In other words, the atavistic model should emphasise that tumours represent a pseudo-multicellular neotissue, rather than a collection of unicellular tumour cells. Indeed, it can be considered as a kind of biofilm, whose life and fate depend on Darwinian and ecological principles. Contrary to unicellular or multicellular organisms, pseudo-multicellularity does not refer to a single organism but to a community of organisms, which display multicellular biological traits. These features preceded multicellularity and some of them prepared the major evolutionary transition, which lead to true multicellularity. It is important to insist on the pseudo-multicellular mode of life, because ever since the emergence of unicellular life, biofilms are the rule, rather than the exception.2 The 3430-million-year-old stromatolites found in Pilbara Craton in Australia indicated an early appearance of pseudo-multicellularity.3 The conventional scenario for the major evolutionary transition to a multicellular organism probably follows the three-state transformation series: social (pseudo-multicellular) prokaryote that evolved to social (pseudo-multicellular) protist, which evolved to a multicellular organism.4 Thus, backward evolution would certainly transform a “multicellular” cell into a “pseudo-multicellular” cell. Within a solid tumour only single migrating cells, which evade anoikis, can be considered as pure “unicellular” cells.

Genomic phylostratigraphy has shown that many genes considered as specific of multicellular organisms and are pointed out by the atavistic model were already present in unicellular organisms before metazoan appearance.5 Among these genes, we find genes involved in cell death, adherence, and tight and gap junctions. This fact clearly underlines the importance and primacy of the unicellular social mode (pseudo-multicellularity) throughout natural evolution. Genes involved in cancer have pseudo-multicellular and multicellular evolutionary origins rather than pure unicellular evolutionary origin.

Ceaseless proliferation is the most characteristic feature of cancer. But, this behaviour is rarely adopted by unicellular organisms in nature. In addition to cell communication, cell-to-substrate and cell-to-cell adhesions, earlier unicellular organisms (prokaryotes and protists) acquired a variety of anti-proliferative capabilities (cell cycle negative regulation, programmed cell death, contact-dependent inhibition, toxin-antitoxin, etc.) through the pseudo-multicellular mode of life and responses to selective pressure.6,7 Indeed, exponential growth may lead to species extinction due to starvation or destruction of the protective biofilm. Earlier prokaryotes inevitably faced this problem and natural evolution proposed different solutions to circumvent them, which were thereafter fixed by heredity.

Trigos et al.1 underlined that many hallmarks of the malignant phenotype of cancer can be interpreted as resulting from dysregulation of genes and cellular processes that appeared during transition from unicellularity to multicellularity.8 As previously mentioned, numerous genes involved in cancer and multicellular maintenance appeared before this transition.5 These genes certainly appeared in response to selective advantages conferred by the pseudo-multicellular mode of life. These advantages can be briefly summarised as protection from a wide range of environmental challenges. Second, and this is an important question, how can the atavistic model explain the induction of angiogenesis, lymphangiogenesis, axonogenesis, inflammation and immune-suppressing cell recruitment, which are frequently encountered in tumours? In these cases, the “tumours are wounds that do not heal” model seems to perform well.9 Third, high-throughput sequencing technology revealed that we only know half of genes involved in cancer and that these new genes could not be classified using classical cancer hallmarks categories.10

In conclusion, the atavistic model, which rightly focuses on dysregulation and/or loss of multicellularity-associated constraints, undoubtedly represents a powerful model, but it does not take into account other important hallmarks of cancer. It only models a part of the initiation process of carcinogenesis. In addition to what has been said above, ecological (cooperation, competition, and predation) and parasitic interactions between cells should be included in a global model of cancer.

References

  1. 1.

    Trigos, A. S., Pearson, R. B., Papenfuss, A. T. & Goode, D. L. How the evolution of multicellularity set the stage for cancer. Br. J. Cancer 118, 145–152 (2018).

    CAS  Article  Google Scholar 

  2. 2.

    Davey, M. E. & O’Toole, G. A. Microbial biofilms: from ecology to molecular genetics. Microbiol. Mol. Biol. Rev. 64, 847–867 (2000).

    CAS  Article  Google Scholar 

  3. 3.

    Allwood, A. C., Walter, M. R., Kamber, B. S., Marshall, C. P. & Burch, I. W. Stromatolite reef from the early Archean era of Australia. Nature 441, 714–718 (2006).

    CAS  Article  Google Scholar 

  4. 4.

    Niklas, K. J. The evolutionary-developmental origins of multicellularity. Am. J. Bot. 101, 6–25 (2014).

    CAS  Article  Google Scholar 

  5. 5.

    Domazet-Loso, T. & Tautz, D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoan. BMC Biol. 8, 66 (2010).

    Article  Google Scholar 

  6. 6.

    Bayles, K. W. Bacterial programmed cell death: making sense of a paradox. Nat. Rev. Microbiol. 12, 63–69 (2014).

    CAS  Article  Google Scholar 

  7. 7.

    Claessen, D., Rozen, D. E., Kuipers, O. P., Sogaard-Andersen, L. & van Wezel, G. P. Bacterial solutions to multicellularity: a tale of biofilms, filaments and fruiting bodies. Nat. Rev. Microbiol. 12, 115–124 (2014).

    CAS  Article  Google Scholar 

  8. 8.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  Google Scholar 

  9. 9.

    Dvorak, H. F. Tumors: wounds that do not heal: similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  Article  Google Scholar 

  10. 10.

    Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041 (2017).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Pascal Jézéquel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jézéquel, P., Campone, M. Comment on ‘How the evolution of multicellularity set the stage for cancer’. Br J Cancer 119, 133–134 (2018). https://doi.org/10.1038/s41416-018-0091-0

Download citation

Search

Quick links