Fundamental Science: The paradoxes of cancer

Like any human being, you are made up of trillions of cells, most of which are constantly dividing. As you read this text, many of your cells are dividing, and each division carries the risk of generating a mutation in the DNA. While most mutations are harmless or correctable, some may give the cell the ability to proliferate uncontrollably, resulting in cancer.

Tumor cells are selfish entities that seek immortality, while threatening the life of the body they inhabit. If, on the one hand, thanks to advances in science it is much easier to survive cancer today, on the other hand, it is increasingly common to have this disease. New estimates suggest that in the coming decades, one in two people will be diagnosed with a malignant tumor at some point in their lives.

Although factors related to our lifestyle influence the increase in cases, the main responsible for this incidence is our increasing life expectancy. The probability of developing cancer grows as cells divide and accumulate mutations, which occurs predominantly as we age: about 60% of cases affect people over 65 years of age. According to this reasoning, animals that have more cells than humans and that live longer should have a higher risk of developing cancer, and the opposite would also be true.

Surprisingly, that’s not how it works. Nearly 50 years ago, British researcher Richard Peto observed that, despite mice having 1,000 times fewer cells than humans and a life expectancy 30 times shorter than ours, the risk of mice and humans developing cancer was similar. This observation became known as the Peto Paradox.

This paradox can be observed in several animal families. The Greenland whale, for example, weighs 100 tons and lives over 200 years, but there are no records of a malignant tumor in this species. Researchers have recently discovered changes in your cells in genes associated with DNA repair and the regulation of cell division and metabolism. Similarly, the humpback whale has gene duplications that may favor the death of tumor cells and the activation of the immune system.

Already in elephants, whose cancer rate is only 5%, many extra copies of a tumor suppressor gene, called TP53 – it encodes the production of the p53 protein, the main regulator of our cell division cycles, “the guardian of the genome”. DNA damage activates such a protein, which will trigger a sequence of events in the cell in an attempt to repair the damaged DNA, stop cell growth, or cause the modified cell to die, preventing it from dividing and passing on acquired mutations. In elephants, if one copy of this gene becomes inactive, there are many others that can take over and protect the organism.

In recent years, data on tumor rates and cell function in several species of the animal kingdom have helped us to understand the important role of evolution in the development of cancer. It is believed that large, long-lived animals needed to develop compensatory adaptations so that their robust numbers of cells could continue dividing for decades without generating tumors.

Evolution may also explain why some mammals have higher rates of cancer than others, and the key to the answers may lie in pregnancy. In some placental mammals, such as humans, the fetal part of the placenta invades maternal tissue to reach the blood vessels of the uterus and obtain nutrition for the fetus. There are great similarities between the invasion of the uterine placentas and that of cancer in the tissues of the body, and animals with this type of placental invasion are more likely to develop more invasive tumors.

In agreement with these findings, several genes related to placental invasiveness were also highly expressed in tumor metastases. One hypothesis is that, with the emergence of placental mammals 100 million years ago, mechanisms that would allow the maternal immune system to tolerate the invasion of fetal tissue could have been selected, bringing the burden of a greater risk to develop tumors.

There are still many answers left for us to resolve the paradoxes of cancer. Studying how different animals suppress the development of tumors could provide resources for the treatment in humans to be even more effective in the coming decades.

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Rossana Soletti is a professor at UFRGS and a researcher in the field of oncobiology.

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