3 cancer is called the Peto’s paradox (footnote 1), named af ter the Engl i sh statistician and epidemiologist Richard Peto [2]. Simply terming the phenomenon as a paradox is not enough for scientists – currently, there are two general explanations for the anomaly, with the first one being genetics. The TP53 gene, which encodes p53 proteins, is one of the tumor suppressor genes. These proteins are located at the nuclei of cells, monitoring the DNA. When the DNA is damaged, p53 proteins will pause the cell cycle and activate other DNA repair genes if the damage is repai rable, otherwise cel l death will be induced to prevent further replication and perpetuation of the potentially harmful mutated DNA [3, 4]. Previous studies have demonst rated that loss-of-function mutations in TP53 (which in turn produces p53 proteins that are not fully functional) was found in over 50% of human cancers, suggesting the impo r tance of th i s mechan i sm i n cance r suppression [5]. Subjected to higher mutation r isks, elephants have evolved to contain 20 copies of the TP53 gene, whereas humans only have one copy [6]. This means the extra copies in elephants can compensate for mutated ones, retaining the ability to kill cancerous cells in the case of mutations. In contrast, if the only TP53 gene in humans is mutated, it can lead to an inheritable genetic condition called the Li-Fraumeni Syndrome, in which the individual is susceptible to a wide range of cancers at a young age [7]. In addition to the number of TP53 copies, a recent study also revealed that elephants had historically restored the function of an ancient, non-functioning gene remnant called LIF6. In response to DNA damage, LIF6 proteins can be activated by p53 proteins to effectively induce apoptosis and kill abnormal cells before they become cancerous [8]. This could be the reason why elephant can evol ve i n t o t h e o n l y paenungulate (footnote 2) with an exceptionally large body si ze whi le being resi l ient to cancer. Therefore, larger organisms could have unique tumor suppression mechanisms to genetically fight against cancer. Hypertumors, the tumors of tumors, are the second explanation of Peto’s paradox. Unl ike normal cel ls, cancerous ones are competitive and not cooperative in nature. This is characterized by tumor angiogenesis, the formation of blood vessels to provide ex t ra blood suppl y (wi th ox ygen and nutr ients) for prol iferation [9]. Based on this fact, it is not hard to imagine that any tumor would try to capture resources by any means. Research had predicted that the competing nature of cancer cells favor the formation of parasitic hypertumors, which feed on the parent tumor’s blood vessels [10]. Before a tumor can grow to a lethal size in large organisms, hypertumors would have emerged and stop the evil plan of the parent tumor by depriving their resources and keeping them at a sublethal size [10]. Nevertheless, this cannot be achieved in smaller organisms because a small tumor, which takes much less time for a single cancer cel l to develop to, is already l ifethreatening to the host. Hypertumors simply
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