The secret that elephants are less susceptible to cancer

Cancer is one of the major health threats faced by mammals during their lives. According to statistics released by France's International Agency for Research on Cancer in 2021, there are nearly 20 million new cancer cases and 10 million cancer deaths worldwide every year. Globally, 1 in 5 people are at risk of developing cancer in their lifetime, and the incidence of elephant cancer is relatively low. If we find out why elephants are less susceptible to cancer, we may be able to provide useful references for human cancer prevention and treatment.

Elephants rarely get cancer

Although exposure to toxic compounds, smoking, air pollution, staying up late, aging, and a variety of factors can cause cancer, all cancers are essentially caused by random mutations in animal DNA, especially in genes associated with tumorigenesis. Of course, tumor cells are not formed by one or several random DNA mutations, but require the continuous accumulation of random DNA mutations to lead to cell carcinogenesis, that is, cell growth and proliferation are not controlled by the body. When a person goes from a fertilized egg to adulthood, their DNA will be replicated about 30 trillion times, each of which can lead to cancer-causing mutations.

Theoretically, the incidence of cancer in different mammals is related to their size, because the larger the animal, the greater the total number of cells in the body, the greater the number of cell divisions, and the higher the number of random mutations in cancer-causing DNA. For example, as the largest animal on land, should the elephant have a higher cancer rate than other mammals such as mice and humans? The answer is no. This is known as Pito's paradox.

African elephants walking by the lake. Elephants weigh about 40 times as much as humans, have a lifespan similar to that of humans, and have a lifetime cancer incidence of only about 3%. Visual China|Figure

The Pito paradox was proposed by the British epidemiologist Richard Peto in the 70s of the 20th century. Professor Pito, while conducting epidemiological studies of cancer, observed that although mice have about 1,000 times fewer cells and 30 times shorter lifespans than humans, there is no significant difference in their risk of cancer, that is, there is little relationship between the incidence of cancer in different species of animals and their relative size or longevity. Pito speculates that there may be an intrinsic biological mechanism that protects cells from cancer as they age and expand.

Elephants weigh 40 times more than humans, have a lifespan similar to that of humans, and have a lifetime cancer incidence of only about 3% and a mortality rate of less than 5%, while human cancer mortality can be as high as more than 25%, and the mortality rate in mice can even reach 50%-90%. Why is cancer incidence and mortality so low in giant elephants? Many biologists are interested in this question and decide to find out, but it is a pediatric oncologist who is the first to find out.

It turns out that there are secret weapons

Dr. Joshua Schiffman from the University of Utah is a pediatric oncologist who has been researching the mechanisms of pediatric tumors and drug development. By chance, he first heard about the Pito paradox during a lecture, and the scientist who gave the lecture also explained that he had discovered multiple copies of a gene called P53 in the elephant genome.

This aroused a great deal of interest in Scheefman. As an oncologist, Scheffman is very familiar with the P53 gene. The P53 gene is a well-known tumor suppressor gene that is present in almost all mammalian genomes, but only one copy of P53 is present in the human genome.

There are two main types of genes related to cancer in animals, one is proto-oncogenes and the other is tumor suppressor genes. These two types of genes are originally normal genes, the expression products of proto-oncogenes generally play a role in promoting cell growth and proliferation, while the expression products of tumor suppressor genes will inhibit cell growth to prevent cells from growing too fast, and some tumor suppressor genes are also responsible for killing "sick", "senescent" or other "abnormal" cells, so that these problematic cells "self-destruct" in situ - apoptosis. Therefore, when stimulated by an unfavorable environment, mutations may occur in either proto-oncogenes or tumor suppressor genes, which may lead to uncontrolled cell growth and proliferation, indefinite division, and more and more tumor cells, which will eventually lead to cancer.

The P53 gene is one of the most important tumor suppressor genes associated with the development of human cancer. However, it was first mistaken for a proto-oncogene, as scientists detected the P53 protein in more than half of tumor cells. With the deepening of research, scientists found that this P53 gene is present in all mammalian cells, but the P53 gene sequence of tumor cells is different from that of normal cells. In other words, the P53 gene of the tumor cells has been mutated and cannot perform its normal functions, resulting in uncontrolled tumor cells that need to "self-detonate", and cancer will follow. Studies have shown that children with oncogenic mutations in the P53 gene develop multiple childhood cancers, with a lifetime risk of 73% for men and nearly 100% for women.

Schuffman's team studied 36 different mammalian genomes and found that most mammalian cell genomes have a unique P53 gene, but the African elephant genome has as many as 20 copies of the P53 gene, and the Asian elephant genome also has 15-20 copies of the P53 gene. Of course, these P53 genes are not identical, only one of them has a complete structure and function, and the others are slightly different, being a reduced version of the normal P53 gene, which can also express structurally defective P53 protein analogues and perform all or part of the physiological functions of P53 protein.

At the same time, the team of Professor Vincent Lynch, an evolutionary geneticist at the University of Chicago, also conducted an in-depth study of the P53 gene in elephants from an evolutionary perspective, and they compared the genomes of 61 different mammals and found that most animals have only one normal copy of the P53 gene, a few animals contain several copies of the P53 gene, and proboscis animals contain more than 10 copies of the P53 gene. In Proboscis animals, in addition to African elephants and Asian elephants, there are about 14 copies of the P53 gene in the extinct woolly mammoth and Colombian mammoth, so the researchers speculate that multiple copies of the P53 gene were formed 65 million to 25 million years ago. During this period, proboscis animals evolved in the direction of large-scale, and multiple copies of the P53 gene could effectively reduce the cancer prevalence of large proboscis animals, so that elephants could not only grow into behemoths, but also live a long and healthy life, so multiple copies of the P53 gene may play an important role in the evolution of proboscis animals such as elephants.

How to exert your power

So, how does multiple copies of the P53 gene protect elephants from cancer?

First, let's look at the normal function of the P53 protein, the product of P53 gene expression. The P53 protein, also known as the "guardian of the genome", has a primary function of maintaining DNA integrity. When cells are subjected to adverse environmental stresses that cause DNA damage, they either attempt to repair themselves or undergo apoptosis. Once there are some errors in the DNA replication process that can lead to cell carcinogenesis, and these errors are not repaired in time or cannot be repaired, the P53 protein initiates the apoptosis process through a series of complex pathways, allowing these potential tumor cells to "self-destruct". With the protection of the normal function of the P53 protein, the probability of tumor cells will be greatly reduced, so that the occurrence of tumors can be inhibited, so the real identity of the P53 gene should be a tumor suppressor gene. At the same time, the P53 gene also plays an important role in body development, aging, and cell differentiation.

In order to verify the role of multiple copies of the P53 gene, Schiffman's team conducted a comparative test between elephant cells and human cells, and after these cells were subjected to ionizing radiation (damaging the DNA of the cells), they found that the apoptosis rate of elephant cells was significantly higher than that of human cells, showing that multiple copies of the P53 gene corresponded to more P53 protein, which accelerated the apoptosis of elephant cells. At the same time, Professor Lynch's team also confirmed that overexpression of multiple copies of these P53 genes can indeed significantly enhance the sensitivity of elephant cells to DNA damage and more easily induce apoptosis. Later, Scheffman's team and Lynch's team also found that some reduced copies of P53 genes also had the activity of promoting apoptosis although the expressed proteins were structurally deficient in normal P53 proteins.

A study published in 2022 further analyzed how multiple copies of the P53 gene can help elephants avoid cancer. The researchers believe that one pathway is that multiple copies of the P53 gene can offset the risk of oncogenic mutations in the normal P53 gene, and the other way is that although the multiple copies of the P53 gene are different copies of the normal P53 gene and the protein products they express are also different, they can respond to DNA damage in a variety of different ways, thereby improving the efficiency of DNA repair and the apoptosis of those cells that cannot be repaired.

Therefore, we can understand that it is precisely because the elephant genome has multiple copies of the P53 gene, the so-called "more people are stronger", and the elephant cells have more P53 protein monitoring and protection. Once the elephant cells make irreparable errors in the DNA replication process, these P53 proteins will immediately respond and quickly start the apoptosis program, so that the cells that have problems will all "self-destruct" and nip the new tumor cells in the bud, which can greatly reduce the probability of tumorigenesis.

Could multiple copies of the P53 gene in elephants help with cancer treatment in humans? That's what pediatric oncologist Joshua Schiffman is concerned about. To that end, Schiffman also founded a biomedical company that plans to use the elephant P53 protein produced by multiple copies of the P53 gene for human cancer treatment. Current preclinical trials have shown that this new drug candidate has the potential to be developed into a new drug for the treatment of human cancer, but more clinical trials are needed to validate it.

Southern Weekly Contributing Writer Tang Bo

Editor-in-charge: Zhu Liyuan