Medicine
Cancer as an evolutionary adaptation and cell survival mechanism
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MPH, MSc
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Cancer can be understood as a disruption of the evolutionary mechanisms that allow millions of cells to cooperate within an organism. The atavistic hypothesis proposes that tumor cells reactivate ancient programs of proliferation and autonomous survival, while losing some of the controls inherent to multicellularity. In this article, we explain an evolutionary perspective on cancer, as a disruption of the balance between unicellular and multicellular mechanisms.
Many of these mechanisms appeared or became consolidated during the evolution of multicellular organisms as it became necessary to control when a cell divides, when it stops, when it differentiates, when it repairs its DNA, when it stays in place, and when it should die. Cancer is thus related to the functional disruption of these programs, partly a regression toward unicellular order, with a loss of multicellular control programs. It can be seen as a reversal of the evolutionary path that allowed millions of cells to form an organism, not a mass of aggregated autonomous cells. Cancer is therefore an inherent risk of this evolutionary architecture. The organism can be seen as a structure that emerges from the evolution of cellular control programs, and cancer, in part, as the loss of this order.
ATAVIC HYPOTHESIS
In a multicellular animal, billions of cells must cooperate, divide only when appropriate, differentiate, die if damaged, and subordinate their reproduction to the entire organism. Cancer can be seen not so much as "damaged" tissue, but as a failure in the systems that evolved to maintain multicellularity. Far from the traditional view of the tumor cell as a "rogue cell" resulting from chaos or the mere random accumulation of mutations, the atavistic hypothesis (Davies & Lineweaver, 2011) proposes that cancer responds to the structured reactivation of a pre-existing genetic program, evolutionarily prior, unlocking primordial genes for proliferation and autonomous survival that predate the control networks of complex organisms.THE MULTICELLULAR PACT
Cancer can thus be seen as a risk of the transition from unicellular to multicellular life. For most of the history of life on Earth, living beings were unicellular organisms. Thus, the cell could be seen as a complete living "organism" in itself; its objective was to survive, feed, divide, and produce offspring. Its entire biology was organized around the limits of its own survival. However, many cells began to cooperate with each other, forming complex organisms, tissues, organs... eventually forming metazoans (animal organisms with cells organized into tissues). Evolution toward multicellularity, however, demanded a new form of communication between cells, and each cell had to cease behaving as an autonomous individual. The cell that integrated into the emerging functions of a complex organism could no longer divide at will or seek its own survival at the expense of the cell group. Thus, a liver, skin, or intestinal cell must obey tissue equilibrium signals, respect boundaries, fulfill a function, and, if necessary, die for the good of the organism.CELLULAR PROGRAMS AND PHYLOGENY
Many pathways overexpressed in cancer do not have the basic function of "producing cancer" per se. Most are normal programs of cellular life: growing, dividing, repairing DNA, responding to stress, capturing nutrients, communicating, adhering, differentiating, or dying. Cancer arises when these programs become activated outside of their functional and organic context, failing to respond to tissue signals and controls.Figure 1.Evolutionary layers of cellular regulation. The oldest pathways regulate the cell's internal physiology: RAS, PI3K, AKT, mTOR, and MAPK control nutrient uptake, growth, anabolism, division, and the response to damage. With multicellularity, mechanisms emerged to integrate each cell into the tissue through adhesion, differentiation, communication, and programmed cell death. Finally, in more complex metazoans, pathways such as JAK/STAT and VEGF, along with cytokines, hormones, and immunity, coordinate organism-wide processes such as inflammation, angiogenesis, and development.
Many of these mechanisms appeared or became consolidated during the evolution of multicellular organisms as it became necessary to control when a cell divides, when it stops, when it differentiates, when it repairs its DNA, when it stays in place, and when it should die. Cancer is thus related to the functional disruption of these programs, partly a regression toward unicellular order, with a loss of multicellular control programs. It can be seen as a reversal of the evolutionary path that allowed millions of cells to form an organism, not a mass of aggregated autonomous cells. Cancer is therefore an inherent risk of this evolutionary architecture. The organism can be seen as a structure that emerges from the evolution of cellular control programs, and cancer, in part, as the loss of this order.
GENETIC EVIDENCE
The evolutionary age of genes can be traced across species. Cancer-related genes are overrepresented at two major evolutionary junctures: the origin of the first cells (greater expression of "selfish" unicellular processes) and the origin of multicellular cooperation and metazoans (which would imply the loss of processes that evolved at this stage to coordinate multicellular evolution). Transcriptomics shows higher expression of genes older than the corresponding normal tissue, consistent with the overexpression of phylogenetically older genes. Some experimental studies have shown that metastatic progression in breast cancer xenografts was associated with the positive selection of loss-of-function mutations in genes related to multicellularity, evolving toward a state more similar to that of embryonic stem cells, with greater clonal proliferative capacity (Chen et al., 2015). This points to a selection of cells with greater activity of evolutionarily ancient programs, characteristic of unicellular stages, along with the loss or dysregulation of genes involved in the multicellular organization of tissue and organ (Trigos et al., 2024).FINAL COMMENTS
Within each human cell, programs from different evolutionary stages coexist. There are very ancient genes, related to independent unicellular life, and more recent genes, related to the cell that forms part of a tissue. Cancer is not simply random damage, but rather the alteration of some key processes in the balance between cell life and tissue life. The atavistic theory thus offers us an interesting framework for understanding a pathology as complex as cancer.
#cancer #evolution
References:
Chen, H., Lin, F., Xing, K., & He, X. (2015). The reverse evolution from multicellularity to unicellularity during carcinogenesis. Nature Communications, 6, Article 6367. https://doi.org/10.1038/ncomms7367
Davies, P. C., & Lineweaver, C. H. (2011). Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Physical biology, 8(1), 015001. https://doi.org/10.1088/1478-3975/8/1/015001
Trigos, A. S., Bongiovanni, F., Zhang, Y., Zethoven, M., Tothill, R., Pearson, R., Papenfuss, A. T., & Goode, D. L. (2024). Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins. Genome Biology, 25, Article 110. https://doi.org/10.1186/s13059-024-03247-1
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