Reduced Cancer Risk throughout the Animal Kingdom

 Genes (Basel). 2024 Jan 18;15(1):118. doi: 10.3390/genes15010118

From Churchill to Elephants: The Role of Protective Genes against Cancer

Annalisa Gazzellone 1, Eugenio Sangiorgi 1,*

Editor: Peixin Dong1

5. Reduced Cancer Risk throughout the Animal Kingdom

Apart from various animal models, the investigations into the cancer-protective effect mediated by genes in the animal kingdom have been explored starting from the observation that some very large animals, such as elephants and whales, with a very long lifespan, present a very low rate of cancer. However, this correlation is not perfect within the same species, such as in dogs, in which larger breeds are generally more prone to cancer development than smaller breeds. Conversely, in species of very small size, such as bats, they tend to be more cancer-resistant than mice, despite having similar sizes. Another interesting species in this respect is the naked mole-rat, which, in spite being a rodent of the size of a mouse, has an extremely long lifespan of up to 30–40 years and is extremely cancer-resistant. These studies aim to determine whether different species, particularly those with longer lifespans than humans, can provide valuable insights into the functioning of the major pathways involved in tumorigenesis, and how evolution solved the Peto’s paradox in those species.

Among the extensively studied animal models, elephants have garnered significant attention. This species exhibits an estimated cancer mortality of 4.81%, which is nearly half the observed mortality rate in humans, which ranges 

from 11% to 25% [71]. This disparity has been associated with elephants possessing 20 copies of the Tp53 gene, which differ in length and sequence content [72]. Notably, in the Loxodonta africana species, recent research has demonstrated that the 20 isoforms of the Tp53 gene feature distinct BOX-I Mdm2-binding motifs [73].

MDM2, an oncoprotein, primarily interacts with TP53, facilitating its degradation. This process ensures TP53 activation only when necessary or in response to cellular damage. The proposed mechanism behind the lower incidence of tumors in elephants revolves around the existence of diverse binding epitopes that interact with Mdm2. These distinct pools of Tp53 proteins result in an enhanced apoptotic response to DNA damage [73]. The variations in BOX-I sequences of Mdm2 hinder the interaction between Tp53 and Mdm2, thereby preventing Mdm2-mediated degradation of Tp53. As a result, Tp53 continues to fulfill its role as the guardian of the genome. Having multiple finely tuned copies of Tp53 prevents cells from attempting to repair irreparable DNA damage, thereby shifting the balance towards apoptosis. This multiple-copy configuration serves as an evolutionary fail-safe mechanism against the loss of a single gene copy, as can occur in humans.

Another species extensively scrutinized for low tumor incidence is the Greenland whale (Balaena mysticetus). 

This species boasts a remarkable lifespan exceeding 200 years and displays a lower tumor incidence despite its size, which entails a larger number of cells and significantly greater replication and repair mechanisms compared to humans.

In this long-lived species, the heightened expression of certain proteins involved in oncogenesis, such as Ercc1 and Pcna, has been observed, suggesting a potential protective role against tumors. Ercc1, an endonuclease involved in DNA damage repair, specifically addresses cross-links and mediates nucleotide excision repair [74]. Activating mutations in the Ercc1 gene have been identified in B. mysticetus [75], while in mice, inactivating mutations in this gene are associated with a higher incidence of tumors [76].

Furthermore, an elevated expression of the Pcna gene has been observed in Greenland whales [75]. This gene encodes a protein that plays a crucial role in supporting polymerase activity during DNA replication and repair processes [76].

The Pcna protein holds significant importance in maintaining the polymerase’s attachment to DNA, thus playing a fundamental role in DNA replication. In instances of DNA damage, this protein undergoes ubiquitination, triggering two DNA repair pathways: homologous recombination and nucleotide excision repair. The suggested mechanism behind the greater resistance to DNA damage and the subsequent lower incidence of tumors in Greenland whales involves the overexpression of the Pcna gene and, consequently, an increased production of the protein.

Similar patterns have been observed in other animal species where the expression levels of Pcna in specific organs show a close correlation with cell proliferation. For instance, in the livers of rats, lower levels of the Pcna protein have been linked to decreased levels of cell regeneration [77].

The naked mole-rat serves as a fascinating example for several reasons [78]. Firstly, it is a very small animal with an extraordinarily long lifespan for its size. Secondly, its longevity likely derives also from an incredible resistance to cancer, mediated by a unique mechanism. While elephants and whales exploit some well-known genes for their cancer-resistant traits, Tp53 and Ercc1, both directly involved in DNA repair, apoptosis, and essential cell-cycle decisions, the scientific perspective shifts significantly when examining the naked mole-rat.

The molecule responsible for this unique resistance is a high molecular weight hyaluronan, a glycosaminoglycan (the primary non-protein molecule in the extracellular matrix), secreted by fibroblasts and produced abundantly by hyaluronan synthase 2 (Has2) during postnatal life [79]. The Has2 protein found in the naked mole-rat differs from the mouse and human sequences, due to the substitution of two highly conserved asparagines with two serines. These alterations occur within the catalytic region, resulting in the enzyme from the naked mole-rat being highly processive and producing very high molecular weight

 hyaluronan.

Fibroblasts from naked mole-rats exhibit early contact inhibition, halting their growth at significantly lower densities. This mechanism is likely mediated by hyaluronan within the extracellular matrix, which directly interacts with Cd44 on the cell surface. This interaction induces early contact inhibition through p16INK4a, resulting in reduced cell proliferation, reduced hyperplasia and metastatic potential, and, on a systemic level, reduced inflammation. Additionally, it acts as an antioxidant, decreasing damage from reactive oxygen species to DNA and proteins, 

and makes cells more prone to apoptosis following 

the loss of tumor-suppressor genes [80,81].

The final confirmation that hyaluronan mediated these effects was achieved by increasing the lifespan of mice and enhancing their cancer resistance beyond that of control mice after expressing the naked mole-rat version of Hsa2. The increased expression of hyaluronan not only extended lifespan but also ensured a healthier one in mice [82] (Figure 4

Figure 4

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Different pathways play a role in protecting animals against tumors. In elephants, the gene Tp53 undergoes amplification, increasing up to 20 copies. The finely regulated multiple copies of this gene, activated by DNA damage, prevent the transformation of cells with significant DNA damage into cancerous cells by 

inducing apoptosis. Similarly, in whales, a comparable effect is achieved through the overexpression of the ERCC1 protein. This overexpression enhances the whales’ capability to repair DNA, contributing to a heightened defense against cancer. Conversely, the naked mole-rat utilizes a completely distinct mechanism for tumor protection. These rodents synthesize an exceptionally large hyaluronan molecule, which induces early contact inhibition in fibroblasts. This process leads to reduced cell proliferation, diminished hyperplasia, decreased inflammation, and a lowered potential for metastasis. Up and down arrows stand for “increased” or “decreased”