Why the uncontrolled growth of abnormal cells
Why are cancer rates in elephants so low?
Cancer is a disease defined by the uncontrolled growth of abnormal cells that have the ability to invade other tissues or spread to a new part of the body (Caulin and Maley, 2011). Cancer develops through somatic evolution, the accumulation of mutations and epimutations of cells through a lifetime. As tumours occur through an assemblage of mutations, an animal with more cells would be thought to have higher risk of mutation, and in turn, cancer. Animals with higher longevity would also be thought to have higher instances of cancer due to a longer time to develop mutations. However, there appears to be no relationship between body size, longevity and cancer, the absence of this correlation is known as Peto’s paradox (Caulin and Maley, 2011). Figure one shows the instances of tumours (%) across a range of species, in accordance with body size and lifespan, displaying Peto’s paradox. Until recently, the mechanisms by which this phenomenon exists has not been tested on animals other than rodents (Abegglen et al., 2015). Abegglen et al analysed 36 mammalian species with varying sizes, lifespans, basal metabolic rates and cancer incidences and found no significant relationship between any of the factors (p>0.05)(see figure 1).
Tumor suppressor genes are crucial in the mitigation of oncogenic mutations (Abegglen et al., 2015). Occurrence of oncogenic mutations is quite prevalent in multicellular organisms, and can be responsible for 20 – 46% of total deaths (Caulin and Maley, 2011; Leroi, Koufopanou and Burt, 2003). The TP53 gene, which encodes the protein P53, has been found to respond to a range of cellular stresses including oncogenic mutations and hypoxia as well as repairing damaged DNA (Soussi and Béroud, 2001). Three cancer cell characteristics are; increased proliferation, suppression of apoptosis, alongside genomic instability, occur as a result of inactivation of P53 (Abegglen et al., 2015). Humans have 1 copy of the TP53 gene, containing two alleles. Evidence supports that damage to one of the two alleles present in the TP53 gene can cause a predisposition to cancer, this is called Li–Fraumeni syndrome. Li-Fraumeni syndrome can also occur owing to germline mutations of processes in the P53 function (Bell, 1999). The TP53 gene, also known as ‘the guardian of the genome’, may have played a vital role in the evolution of large body masses (Sulak et al., 2016).
The African elephant (Loxodonta africana) genome was analysed, these elephants have 19 copies of the TP53 gene. The 19 copies lack true introns, suggesting that they are retrogenes, whole genome sequencing with deep coverage confirmed this (Abegglen et al., 2015). Elephant cells respond to lower levels of DNA damage than other species by signalling apoptosis, presence of the retrogenes in elephant will functionally increase the response of the cell to DNA damage by triggering dependent apoptosis (Abegglen et al, 2015; Sulak et al., 2016). Whilst Abegglen et al, 2015 found the presence of retrogenes and highlight difference in sensitivities between human and elephant cells, they did not suggest the mechanisms by which the copies occurred. Sulak et al, 2016, suggests that a single retro-transposition event followed by repeated rounds of segmental duplication of the TP52RTG gene. The Asian elephant (Elephas maximus) genome contains 15 – 20 TP53 retrogene copies.
By looking at the evolution of Proboscideans and the divergence of L. africana and its relative E. maximus, both have retrogene copies of the TP53 gene. This indicates that the amplification of the TP53 retrogene predates the divergence of the African and Asian elephants which was approximately 6.6 – 8.8 million years ago/MYA. Using molecular phylogenic methods, each duplication event of the TP53 gene were dated, and it was concluded that the initial retrotransposition event took place 64 MYA in the Paenungulate stem-lineage (Sulak et al., 2016). Rapid expansion duplication events 40 MYA correlating with the evolution of large body masses.
Paragraph 3 – the importance of cancer research in elephants
Paragraph 4 – implications
Paragraph 5 – discussion and conclusions
Animal’s with long life spans and large body masses have evolved ways to combat increased cancer risk. Elephant’s cells are particularly sensitive to genomic stress. High sensitivity most likely occurred owing to increased body mass, due to increased pressures, thus, an expanded TP53 gene inventory (Sulak et al., 2016). There are limitations present when studying cancer and apoptosis across species owing to a lack of sufficient sample size. Animals in captivity may have a predisposition to cancer owing to diet, stress and other factors (Abegglen et al, 2015). In recent studies, Peto’s paradox, is slowly becoming unravelled and solved. The discovery of TP53 retrogenes copies is part of the explanation as to why elephants have low cancer rates. Abiotic and biotic pressures and other …(Factors influencing evolution of TP53)
Humans have higher risks of obtaining certain cancers from lifestyle choices, such as smoking, which is proven to predispose you to cancers including; mouth, lung and stomach (cite). Other lifestyle choices, which are food related, or even the area you live can impact your risk of cancers from water pollution leading to food pollution. In 2014/15 percentage of deaths from cancer was 28% in the UK, this has decreased by 14% since the early 1970’s (Cancer Research UK, 2018), possibly owing to increased knowledge of factors influencing risk of cancer and increased knowledge of treatments.