Cancer: is it part of evolution? What can we learn from cancer in animals?

Domestic and wild animals get cancer. Animals, like humans, see an increase in cancer when living in areas of heavy chemical contamination. But, some animal species rarely get cancer; why? And, if any cell could become cancerous, why don’t larger animals have a greater risk of cancer than smaller animals?

Animals far larger than humans–like elephants–rarely get cancer. That must mean their cells somehow fight cancer better than ours. What can we learn from those animals to potentially enhance human cancer therapies? And, what is the connection between evolution and cancer? And, what are the implications for humans?

Featured articles:

*Caulin, A. F., & Maley, C. C. (2011). Peto’s paradox: Evolution’s prescription for cancer prevention. Trends in Ecology & Evolution, 26(4), 175-182. [PDF] [Cited by]

The evolution of multicellularity required the suppression of cancer. If every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared with small, short-lived organisms. The lack of correlation between body size and cancer risk is known as Peto’s paradox. Animals with 1000 times more cells than humans do not exhibit an increased cancer risk, suggesting that natural mechanisms can suppress cancer 1000 times more effectively than is done in human cells. Because cancer has proven difficult to cure, attention has turned to cancer prevention. In this review, similar to pharmaceutical companies mining natural products, we seek to understand how evolution has suppressed cancer to develop ultimately improved cancer prevention in humans.”

*Merlo, L., Pepper, J., Reid, B. et al. (2006). Cancer as an evolutionary and ecological process. Nature Reviews Cancer 6, 924–935. [PDF] [Cited by]

“Neoplasms [a new and abnormal growth of tissue especially as a characteristic of cancer] are composed of an ecosystem of evolving clones, competing and cooperating with each other and other cells in their microenvironment, and this has important implications for both neoplastic progression and therapy.

Selection at the different levels of genes, cells and organisms might conflict, and have resulted in a legacy of tumour-suppression mechanisms and vulnerability to oncogenesis in our genomes.

Most of the dynamics of evolution have not been measured in neoplasms, including mutation rates, fitness effects of mutations, generation times, population structure, the frequency of selective sweeps and the selective effects of our therapies.

Many of the genetic and epigenetic alterations observed in neoplasms are evolutionarily neutral.

Cancer therapies select for cancer stem cells with resistance mutations, although various evolutionary approaches have been suggested to overcome this problem, including selecting for benign or chemosensitive cells, altering the carrying capacity of the neoplasm and the competitive effects of neoplastic and normal cells on each other.

Dispersal theory suggests that high cell mortality and variation of resources and population densities across space might select for metastasis.

There is evidence of competition, predation, parasitism and mutualism between co-evolving clones in and around a neoplasm.

We will need to interfere with clonal evolution and alter the fitness landscapes of neoplastic cells to prevent or cure cancer. Evolutionary biology should be central to this endeavor.

Neoplasms are microcosms of evolution. Within a neoplasm, a mosaic of mutant cells compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs. The evolution of neoplastic cells explains both why we get cancer and why it has been so difficult to cure. The tools of evolutionary biology and ecology are providing new insights into neoplastic progression and the clinical control of cancer.”

*Vazquez, J. M., Sulak, M., Chigurupati, S., & Lynch, V. J. (2018). A zombie LIF gene in elephants is upregulated by TP53 to induce apoptosis in response to DNA damage. Cell Reports, 24(7), 1765-1776. [PDF] [Cited by]

“Large-bodied organisms have more cells that can potentially turn cancerous than small-bodied organisms, imposing an increased risk of developing cancer. This expectation predicts a positive correlation between body size and cancer risk; however, there is no correlation between body size and cancer risk across species (“Peto’s paradox”). Here, we show that elephants and their extinct relatives (proboscideans) may have resolved Peto’s paradox in part through refunctionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. LIF6 is transcriptionally upregulated by TP53 in response to DNA damage and translocates to the mitochondria where it induces apoptosis. Phylogenetic analyses of living and extinct proboscidean LIF6 genes indicates that its TP53 response element evolved coincident with the evolution of large body sizes in the proboscidean stem lineage. These results suggest that refunctionalizing of a pro-apoptotic LIF pseudogene may have been permissive (although not sufficient) for the evolution of large body sizes in proboscideans.”

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