Sloths, armadillos, and anteaters have notably low intrinsic cancer risks compared to other mammals. One theory as to why lies in the evolutionary history of their genome.
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If all living cells across species had the same probability of developing into cancer, then it would be reasonable to assume that organisms with more cells have a higher chance of developing cancer. Similarly, it would be reasonable to assume that organisms with longer lifespans are more likely to develop cancer given that their cells have more time to develop cancer-causing mutations. However, neither of these scenarios is the case. But why?
This is Peto’s Paradox (Caulin and Maley 2011; Caulin et al. 2015; Peto 2015). Despite drastic variations in size and lifespan across species, larger-bodied, longer-living organisms are not more likely to develop cancer than their smaller-bodied, shorter-lived counterparts. An organism with 1000 fold more cells than another organism is not in turn 1000 fold more likely to develop cancer. Likewise, organisms that live twice as long as others are not twice as likely to develop cancer over the span of their lives. This is because larger, longer-living organisms have developed specialized biological mechanisms that have lowered their intrinsic cancer risk. Little is known about the function and cause of these biological mechanisms, but several different hypotheses exist. These hypotheses range from species-specific variations in the DNA-repair systems within cells to the mutational triggers necessary to initiate cancer formation (Lichtenstein 2005). In their paper Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra, Vazquez J. M. et al. attempt to uncover more about these hypotheses and their exact biological bases and effects on organisms across the animal kingdom (Vazquez et al. 2022).
To study the biological phenomena of cancer resistance, Vazquez J. M. et al. chose a branch of mammals known as Xenarthra, more specifically sloths, armadillos, and anteaters, which have evolved surprisingly resilient mechanisms against cancer. These animals were first identified because of ancestral reconstructions that showed their ancestors to have independently grown to immense sizes, like the Glyptodon and Megatherium. Within species, the evolutionary development of larger bodies is generally inhibited by cancer, as increased numbers of cells create more opportunities to form cancerous mutations. Furthermore, analysis of Xenarthra lineages showed that their increase in bodily size also corresponded with increases in their lifespan. Thus, this extreme bodily growth coupled with longer lifespans in the ancestral lineage of Xenarthra tells us there must have been an evolutionary event that allowed these animals to lower their intrinsic cancer risk.
Once these extinct, large-bodied Xenarthra lineages were identified, the genomes of extant Xenarthra lineages were investigated for duplications; more specifically, they were looking for duplications of genes associated with tumor suppression. This was done following previous studies showing elephant species to have low intrinsic cancer risks associated with duplications in tumor-suppressor pathways (Vazquez and Lynch 2021). Over 100 duplications were identified in Xenarthra stem lineages, of which 26 were enriched in tumor-suppression pathways involved in cell cycle regulation, protein folding, intrinsic apoptosis, and regulation of p53 degradation.
This enrichment of tumor-suppressor pathways involved in cell cycle regulation prompted Vazquez J. M. et al. to investigate how cell cycles differ across species. To do this, doubling time data was gathered from primary dermal fibroblasts of sloths, armadillos, anteaters, and several other mammalian species- doubling times refer to the amount of time it takes a cell to completely duplicate its DNA and divide. This data was compared across species, and it was found that sloth doubling times were longer than that of any other mammal tested; however, armadillo and anteater doubling times were similar to that of the other mammals tested. It is hypothesized that the long doubling times of sloths may allow for additional time to correct DNA damage and genomic instabilities which correlate with cancerous mutations. This would explain sloths’ low intrinsic cancer risks.
Furthermore, the enrichment of tumor-suppressor pathways involved in intrinsic apoptosis and the regulation of p53 degradation was investigated to analyze DNA damage responses in Xenarthra. Cell cultures of the Xenarthra lineages as well as other mammal, reptile, and bird species were done to test their response to cellular damage induced by mitomycin C, which is a DNA-damaging agent. These tests found that some species in the Xenarthra lineages showed higher levels of apoptosis in response to lower levels of mitomycin C compared to the other species examined. This data indicates that Xenarthra lineages are particularly sensitive to DNA damage which may further help to explain the low intrinsic cancer risk associated with these species.
As cancer becomes a growing topic of concern around the world, more efforts are being made towards finding better treatment methods. This research provides insightful genomic and ancestral analyses of how organisms have adapted specialized biological mechanisms against cancer development. By deepening the genetic understanding of cancer, more effective treatment options can be created. However, this paper lacks sufficient depth to support some of the claims they’re making. This is something Vazquez J. M. et al. critique about their methodologies- pointing out how claims regarding sensitivity to DNA damage are heavily biased considering only one cell type from one animal of each species was used in their cell cultures. Furthermore, additional research is needed to solidify the foundation for some of the findings presented. The research was limited by a lack of genomic sequencing data and high rates of error in estimating cancer prevalence across species. There are still many holes to be filled in regarding some of the findings that only further research can accomplish. However, this paper is another step towards the advancement of understanding the evolution of cancer in mammals.
References:
Caulin A. F., and C. C. Maley, 2011 Peto’s Paradox: evolution’s prescription for cancer prevention. Trends in Ecology & Evolution 26: 175–182. https://doi.org/10.1016/j.tree.2011.01.002
Caulin A. F., T. A. Graham, L.-S. Wang, and C. C. Maley, 2015 Solutions to Peto’s paradox revealed by mathematical modelling and cross-species cancer gene analysis. Philosophical Transactions of the Royal Society B: Biological Sciences 370: 20140222. https://doi.org/10.1098/rstb.2014.0222
Lichtenstein A. V., 2005 On evolutionary origin of cancer. Cancer Cell Int 5: 5. https://doi.org/10.1186/1475-2867-5-5
Peto R., 2015 Quantitative implications of the approximate irrelevance of mammalian body size and lifespan to lifelong cancer risk. Philosophical Transactions of the Royal Society B: Biological Sciences 370: 20150198. https://doi.org/10.1098/rstb.2015.0198
Vazquez J. M., and V. J. Lynch, 2021 Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk, (A. Rokas, P. J. Wittkopp, S. C. Stearns, and V. Gorbunova, Eds.). eLife 10: e65041. https://doi.org/10.7554/eLife.65041
Vazquez J. M., M. T. Pena, B. Muhammad, M. Kraft, L. B. Adams, et al., 2022 Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra, (A. Rokas, P. J. Wittkopp, and S. C. Stearns, Eds.). eLife 11: e82558. https://doi.org/10.7554/eLife.82558
Article by Tate Weston. Contact the author at tapeterson@davidson.edu
Original Article: Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra
© Copyright 2024 Department of Biology, Davidson College, Davidson, NC 28036
I really enjoyed reading your article. I think you not only gave great background but also explained their methods in a concise way. The experiments Vasquez and his team ran are enlightening and definitely open the door to thinking about possible treatments for cancer using these mechanisms. Lastly, I think you did a great job of providing your view in the sampling issue that the authors bring up. I agree with your position, more samples are needed for a more holistic study of how this adaptation contributes to preventing cancer.
This was a very interesting topic to read about. I wonder if there was some sort of selection event that are enriched in tumor-suppression pathways to evolve. Apoptosis is a method of cell death that the body uses to get rid of unneeded cells & cancer is a result of rapidly growing cells, so I see how higher levels of apoptosis can reduce the chances of developing cancer. I wonder how the results of this study can be used to treat cancer in humans.
This was a very interesting topic to read about and I hope to see more literature published on the subject! I appreciated how you discussed the limitations of the study and how they may be corrected in future research! I would also be interested to know how the cancer rates and tumor suppressor pathways of humans and closely related primates have developed over time as human life expectancy has greatly increased. Since many forms of cancer such as melanoma develop in humans after reproductive age, might these cancers have less selective pressure against them than others such as breast cancer?