04. Of Elephants and Whales and Cancer

04. Of Elephants and Whales and Cancer

Multicellularity is challenging. Life is challenging; to say that all there is to unicellularity is self-regulation and reproduction is a gross understatement. But you only need to regulate single cells, or loose communities of cells. Once you start organizing multiple cells, you need them to function efficiently, as a team. This teamwork can be summarized with five essential features (Aktipis et al., 2017):

  1. Proliferation inhibition
  2. Controlled Cell Death 
  3. Division of Labor
  4. Resource Allocation and Transport
  5. Extracellular Environment Maintenance

The first two are especially pertinent in today's story, as controlling when cells reproduced, and when cells are destroyed, and maintaining that control is essential for multicellular harmony. And once you have a bunch of cells working together in harmony, having one cell, or cell line, going rogue is a disaster. One cell going on it's own, growing, reproducing, and spreading, without coordination:

Cancer.

Cancer is an intrinsic problem of multicellularity. Action must be taken to check for genetic damage that could result in unchecked growth. Countless mechanisms rise up to check for damage, flag damaged cells, and allow a multicellular organism to destroy rampant growths. And these in turn become preoncogenes, new ways for genetic replication to go astray and lead to the death of the organism as a whole to feed the incipient growth.

And so, we come to a challenge. Presume that there is a fixed likelihood that in any given instance of mitosis a mutation can occur. Compound this with a fixed likelihood that such a mutation is of a preoncogene into an oncogene (again, a gene that, if mutated, can lead to cancer; it shares the same route as the term oncologist), and that there is some number of oncogenes that must accrue for all the failsafes to fail. What this essentially means is that as the number of cell divisions increases, the odds will increase that preoncogenes will become mutated into oncogenes, and furthermore the odds enough will have mutated to produce a line of cancer cells, leading to tumorogenesis. 

And, since the more cells an organism has, the larger it is, a larger organism is expected to have a higher rate of cancer. In the same turn, animals with longer lifespans (and thus a larger number of cell replication events over that lifespan) are also seemingly vulnerable to the same higher rates (Peto, 1977, 2015).

Except when they don't.

Peto's Paradox.

From Abegglen  et al. , 2015. Data taken from zoo necropsies, showing a fairly constant low cancer rate. Tasmanian devils are a notable exception, due to various factors not relevant here, but quite interesting nonetheless (they have a contagious face-cancer problem)

From Abegglen et al., 2015. Data taken from zoo necropsies, showing a fairly constant low cancer rate. Tasmanian devils are a notable exception, due to various factors not relevant here, but quite interesting nonetheless (they have a contagious face-cancer problem)

 

When examining large animals, there are two major groups that come up: Proboscideans and Cetaceans. Both groups also have rather long lifespans, and so these are the focus of the paradox. Recent studies have shown that in these organisms, as well as many others, there are atypically high numbers of various genes involved mediating cell-growth and regulating controlled cell death. In elephants and their kin, the gene TP53 (and more frequently referred to certain circles as p53) exists in over a dozen copies (Abegglen et al., 2015; Perez and Komiya, 2016; Sulak et al., 2016). p53 is involved in controlled cell-death mechanisms in response to DNA damage, and can be involved in halting the cell cycle (Lowe et al., 1993; Heinrichs and Deppert, 2003). Conceptually, what this means is that when there is a mutation of one of these pre-oncogenes, there is an abundance of built in redundant backups that the cells will still be kept in check. Meanwhile, in our whales, (Keane et al. 2015), a whole host of genes relating to cancer, aging, and development, have notable duplications and/or deletions. If we begin to parse through the genomes of various organisms, we start to see that various tumor-suppressing genes are amplified all over the place, with seemingly multiple independent innovations across the mammalian phylogeny.

From Caulin  et al.  (2015). I have no idea what is going on with microbats.

From Caulin et al. (2015). I have no idea what is going on with microbats.

One element thought to partially explain this in addition to the various incidences of gene duplication is that a major factor in cancer initiation is the rate of metabolism, and larger organisms typically also have larger, slower growing cells, which helps mediate this element of cancerogenesis (Maciak and Michalik, 2014). It seems that major selective pressure exists across animal taxa selecting for genes to help keep cancer to a minimum until postreproductive age, which is in and of itself not terribly surprising, but the effectiveness of this is remarkable when we deal with the much larger and/or longer-lived organisms (Gorbunova et al., 2014) . It seems that any means that can work will work in these organisms, and so in every instance a new set of solutions has arisen to address a singular common problem of multicellularity. Multicellularity is a 1.5 billion year old innovation, and it's success has been dependent on its controllibility. 

References

Abegglen, L. M., Caulin, A. F., Chan, A., Lee, K., Robinson, R., Campbell, M. S., … Schiffman, J. D. (2015). Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA, 314(17), 1850

Aktipis, C. A., Boddy, A. M., Jansen, G., Hibner, U., Hochberg, M. E., Maley, C. C., & Wilkinson, G. S. (2015). Cancer across the tree of life: cooperation and cheating in multicellularity. 

Caulin, A. F., Graham, T. A., Wang, L.-S., & Maley, C. C. (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(1673), 20140222–20140222. 

Gorbunova, V., Seluanov, A., Zhang, Z., Gladyshev, V. N., & Vijg, J. (2014). Comparative genetics of longevity and cancer: insights from long-lived rodents. Nature Reviews. Genetics, 15(8), 531–40. 

Heinrichs, S., & Deppert, W. (2003). Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals. Oncogene, 22(4), 555–71. https://doi.org/10.1038/sj.onc.1206138

Keane, M., Semeiks, J., Webb, A. E., Li, Y. I., Quesada, V., Craig, T., … DeMagalh??es, J. P. (2015). Insights into the evolution of longevity from the bowhead whale genome. Cell Reports, 10(1), 112–122. 

Lowe, S. W., Ruley, H. E., Jacks, T., & Housman, D. E. (1993). p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell, 74(6), 957–67.

Heinrichs, S., & Deppert, W. (2003). Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals. Oncogene, 22(4), 555–71. https://doi.org/10.1038/sj.onc.1206138

Perez, R. P., & Komiya, T. (2016). TP53 Gene and Cancer Resistance in Elephants. JAMA, 315(16), 1789–90. 

Peto, R. (1977). Epidemiology, multistage models, and short-term mutagenicity tests. Origins of human cancer4, 1403-1428.

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(1673). 

Sulak, M., Fong, L., Mika, K., Chigurupati, S., Yon, L., Mongan, N. P., … Lynch, V. J. (2016). TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife, 5(September2016), 594–597. 

Wu, C.-I., Wang, H.-Y., Ling, S., & Lu, X. (2016). The Ecology and Evolution of Cancer: The Ultra- Microevolutionary Process.

05. 5.5 Ma of Darkness

05. 5.5 Ma of Darkness

03. Sunlit Slugs