Cancer be related to the higher frequency of TP53

Cancer is the name given to a collection of 200 related diseases
(Tarver, 2012) that are responsible for 20–46% of total animal deaths (Caulin,
2012) accounting for 10% of all human deaths (Tarver, 2012). There are many
contributing factors to its onset, including genetic and environmental
influences. Despite affecting all animals, cancer rates differ greatly between species.
Being virtually nonexistent in the Naked mole-rat (Heterocephalus glaber) (Hooper,
2013) and decimating the Tasmanian Devil (Sarcophilus harrisii) with 70% of its population being
killed in the past decade by Devil
facial tumour disease- a non-viral clonally transmissible cancer (Nagy, 2007).
Elephant (Loxodonta
Africana/Elephas maximus)
cancer rates are of particular interest in the scientific community, as compared
to other mammals they are very low, going against the typical assumption that larger
animals, having more cells will see higher rates of mutation in their DNA and
as consequence suffer elevated rates of cancer. This is thought to be related
to the higher frequency of TP53 genes elephants possess (Abegglen, 2015).

Cancer at a glance
is the uncontrolled division of cells, where signals of apoptosis (programmed
cell death) are ignored leading to the formation of tumours, damaging
surrounding tissue e.g. through oxygen starvation. There are many forms of cancer,
all of which have unique characteristics (Sudhakar, 2009) e.g. Leukemias are cancers which begin in the blood forming tissue of bone marrow and
do not form solid tumours. Mutations within tumour suppressor genes and proto-oncogenes
are widely recognised as the cause of cancer. There are more than 40 human proto-oncogenes
(Chial, 2008) and these function to safeguard tissues and organs, by encoding
for proteins necessary for cellular homeostasis (Shortt, 2012). Conversely oncogenes
(the mutated version of a proto-oncogene, routinely dominate) demonstrate
increased production of these regulatory proteins, resulting in uncontrolled
cell proliferation paired with irregular cell differentiation, and inhibition of cell death (Chial, 2008); all
characteristic and defining of cancer cells. In contrast to this tumour
suppressor genes encode for proteins that inhibit cell proliferation by
inducing apoptosis (Cooper, 2000) often in relation to the same regulatory
pathways which are stimulated by the products of oncogenes (Testa, 2013). Consequently
a mutation in these genes, result in a decreased production of regulatory
proteins, leading to increased cell division and the likely formation of a tumour (Cooper, 2000).

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Using the information
above it would be assumed that elephants have a higher risk of cancer in
comparison to smaller animals, as their cells have divided many more times,
consequently should possess more random DNA mutations predisposing to a higher likelihood
of developing cancer (Nagy, 2007). Yet in looking at the rates of cancer, globally
1 in 3 people will develop a form of cancer (Chial, 2008) with a mortality rate
of upto 25% (Tarver, 2012). This contrast elephants where there is only 4.81% cancer
mortality rate (Aacr, 2015), despite
an excess of 1000 times more cells (Caulin, 2012) and being 100× larger
(Tollis, 2017). This difference in rates of cancer between species laid the
basis for ‘Peto’s paradox’, which identifies the lack of correlation between
body size, lifespan and cancer incidence (Sulak, 2016) despite the supposition
that every cell has an equal chance of becoming cancerous, and larger,
long-lived organisms should have an increased risk of developing cancer through
the natural accumulation of mutations (Caulin, 2012).

Research has
revealed a direct link between the TP53 gene (a tumour suppressor gene) and
incidence of cancer in elephants, due to its associated function in apoptosis.
TP53 encodes for P53 (Callaway, 2015), a protein which binds to DNA stimulating
the production of the protein P21. This interacts with the protein CDK2, forming
a complex which blocks the cell from entering the next stage of cell division
(Vogelstein, 2010). As a result cell proliferation is controlled (Haupt, 2017),
and damaged cells undergo a programmed cell death preventing the growth/formation
of tumours. Contrary to this mutated TP53 is the most frequently altered gene in cancer patients, playing a role in
up to 50% of all cancers (Haupt, 2017).  When mutated, P53 cannot successfully
bind to DNA and as a consequence P21 is not made available to act as a ‘stop
signal’ for cell division (Vogelstein, 2010) thus cells divide irrepressibly
forming tumours (Abegglen, 2015). Adding
to this mice genetically altered to carry additional copies of TP53 were found to possess an
enhanced response to DNA damage (Tollis, 2017; Caulin, 2012).

Humans contain 1
copy (2 alleles) of the TP53 gene
(Abegglen, 2015), where absence/mutation of 1 functional allele leads to
Li-Fraumeni syndrome (LFS), an autosomal dominant mutation (Abegglen, 2015), which gives rise to
an elevated cancer risk of 50% by age 30 and 90% by 60, compared to the general
population where there is only 1 % chance of developing cancer by 30 (Sorrell,
2013). A number of strategies have been
explored to target TP53-associated
cancers and improve outcomes e.g. using Advexin (a genetically modified virus
carrying the TP53 gene) where one patient was reported to have responded
and demonstrate anticancer activity (Nemunaitis,
2008). Apoptosis rates of damaged cells which may lead to cancerous tumours
through irregular function is 2.71% in humans with LFS, 7.17% in healthy humans
and 14.64% in elephants (Abegglen,
2015). This is because while humans have 1 copies of TP53, elephants
have at least 20 (Aacr, 2015), including 19 retrogenes (Sulak, 2016; Greaves,
2015) which are distinctly different
(Aacr, 2015) but only a few are transcribed (Sulak, 2016), as a result expression
of this gene is more frequent even in the case of a mutation, as there will
still be several to function appropriately. Resultantly apoptosis of damaged
cells is more efficient in preventing uncontrollable cell division. As
reflected by the response to DNA damage following ionising radiation where elephant
lymphocytes underwent apoptosis at a significantly higher rate compared to
human lymphocytes (Abegglen, 2015).
This explains why both the incidence and mortality rate of cancer in elephants
is lower compared to humans, as possessing more copies of the TP53 gene
elephants are able to combat cell proliferation to a higher degree even in the
case of mutation due to availability of several copies and as a whole are
better equipped to deal with DNA damage (Sulak, 2016).

 Another defence elephants
posses against cancer, giving low rates, are replica copies of the LIF gene encoding for leukaemia inhibitory factor (Vazquez, 2017) – a signalling protein involved in
fertility and reproduction. All mammals have one LIF gene but only within elephants
are there 11 duplicates, suggesting this form of cancer resistance is lineage
specific (Tollis, 2017).  Almost all are pseudogenes
(genes rendered useless through mutation) however present in elephants is the LIF6 gene (Vazquez,
2017), which dissimilar to others has not accumulated random mutations.
This gene is activated and regulated by P53, and when expressed triggers apoptosis of damaged cells
through the creation of leaks in the membrane surrounding the mitochondria.
Therefore allows the efficient elimination of potentially malignant cells (Vazquez, 2017) that is not possible in other mammals.

Moreover despite elephants possessing these defences against
cancer, there are possibly other mechanisms which could play apart to influence
low rates. As advocated by evidence from the Whale species where mass ranges
greatly from the Vaquita (Phocoena sinus)
(30–55?kg) to the Blue Whale (Balaenoptera musculus)(?150,?000?kg),
yet no correlation between cancer incidence and size has been distinguished
(Nagy, 2007), supporting ‘Peto’s paradox’. However whales do not posses multiple
copies of the TP53 (Sulak, 2017) gene
nor the LIF6 gene, suggesting alternate factors are in place; as abiding by the
fact  larger organisms have potentially
more carcinogenic cells (Nagy, 2017),  the
blue whale should be extinct due to their size and associated risk of
developing cancer (Caulin, 2012).  Therefore disclosing how other mechanisms may
be in place to defend against cancers (Greaves, 2015), which are undiscovered.  Another animal which provides evidence for
external influence on cancer rates is the Naked Mole-Rat, which had its first
recorded incidence of cancer in February of 2016. This extremely low incidence
of cancer is a consequence of the Naked Mole-Rat secreting a long sugar polymer
called high-molecular-mass Hyaluronan (Hooper, 2013), causing hypersensitivity
to contact inhibition (Tollis, 2017), preventing cells from overloading and
forming tumours (Hampton, 2011). Showing how other factors are active in suppressing
cancer (Tollis, 2017) and may also be responsible for low rates of cancer in elephants
but undiscovered. Furthermore there are multifaceted links between metabolism
and cancer (Donaldson, 2004) , e.g. activated oncogenes and inactivation of
tumour suppressors alter metabolism inducing aerobic glycolysis causing the
resultant building of new cancer cells (Dang, 2012), contrary to caloric
restriction which is protective against the development of cancer by reduction
of oxidative stress (Dang, 2012) Again revealing how other factors may be present
to influence low rates of cancer in elephants including diet (Donaldson, 2004).

In conclusion elephant cancer rates are identifiably low
supporting ‘Peto’s paradox’ that there is no correlation between body size and
incidence of cancer. This is because they posses multiple copies of the TP53
gene as well as the LIF6 gene (Vazquez, 2017). Numerous
copies of the TP53 gene (Abegglen, 2015) where there is usually only 1 or 2 copies in
mammals (Abegglen,
2015), means that within the elephants even if the of case mutation, there
are a sufficient number of copies to be expressed, and so control cell
proliferation and prevent rapid ungovernable cell division, through the
induction of apoptosis averting the development of tumours. However other
influences may play a  part to influence
the rate of cancer within elephants, as suggested by cancer rates of other
mammals including the Blue Whale (the largest living animal on earth) which has
similar cancer rates to humans, supporting ‘Peto’s paradox’, despite not possessing
multiple copies of the TP53 gene (Sulak,
2017), implying that there are possibly undiscovered influences to low
cancer rates and that multiple copies of TP53 cannot be the only explanation
(Callaway, 2015).

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