Nature’s largest animals may have found a way to sidestep cell malignancy, says S.Ananthanarayanan.

The world, in 2018, saw 17 million cases of cancer and 9.6 million cancer deaths. Cancer is the second largest cause of death, after respiratory diseases – every sixth death in the world is due to cancer. The organization, Cancer Research UK, says that by 2040, we expect to have 27.5 million new cases each year.

While there is progress in control and cure of cancer, lifetime risk of cancer and survival of late stage patients has not improved. The curative process sometimes leads to persistence of cancer. As cancerous tumours contain billions of cells, there are often some that resist therapy, and therapy selects these for survival. With this, and the heavy load that cancer places on society, prevention, rather than cure, is the priority. The journal, Scientific Reports, carries a paper by Leonardo oña and Michael Lachmann, from Osnabrück University, Germany and Santa Fe Institute, USA, which examines a proposed natural mechanism that limits the growth of cancer cells in organisms

The background to the study is an observation, known as Peto’s Paradox>/b>, that large animals have less cases of cancer than, according to theoretical considerations, they should. Cancer is known as a disease where the modification or copy errors that take place during cell division, in some cells, causes those cells to multiply without restraint. The different influences that keep cells from uncontrolled multiplication appear to become deactivated and the results are the tumours and imbalances that we know as cancer.

Now, if it is random changes that occur in some cells that can start a cancerous growth, it is reasonable that organisms that have more cells, or that live longer, and hence see more instances of cell division, should have greater incidence of cancer. Strangely, this is not the case. The number of cells, in the case of a mouse, of a human or an elephant, or a whale, differs by orders of thousands and tens of thousands. The life span too, can differ by a factor of tens to hundreds. The incidence of cancer, however, is almost the same, differing, at most, by a factor of two! It would seem that the blue whale, a thousand times the weight of a human, has developed suppressants of cancer that are a thousand times better than those of humans.

A 2011 paper in the archive of the National Institute of Public Health, which the Scientific Reports paper cites, says, “When wild mice are raised in protected laboratory conditions, 46% die of cancer. Cancer is also responsible for about 20% of dog deaths, roughly 25% of human deaths in the United States and 18% of beluga whale deaths. Rare cases of cancer are discovered in blue whales, giving no evidence of elevated cancer risk in these species. No matter the size or lifespan of the animal, cancer seems to account for approximately the same percentage of deaths.”

Seeking the reason behind this lower incidence of cancer as an organism grows larger, and hence a resolution of Peto’s Paradox, could then lead to a way to contain cancer. The paper in Scientific Reports points out that preventing cancer has been a challenge ever since life evolved beyond the state of consisting of a single cell. It is primarily critical, the paper says, in animals, where cells are able to move to different parts of the body. That the possibility of cancer was a serious issue to sustain species is apparent from the brace of processes that has evolved – the immune system, which, in principle, can detect and cut short signs of malignancy, the shortening of the extremities of DNA to limit cell division, and genes that suppress tumours, as well as the structure of cells need to undergo several genetic changes before they can become malignant.

Another approach to how cancer cells multiply is via the processes that are in play in cell growth. Cells grow with the help of signals, in the form of chemicals, which they send to other cells and receive from other cells. These are the signals, for instance, that set up the channel of blood supply that cells need when they proliferate, and signals which retard or accelerate nutrition, or cell division.

The Scientific Reports paper examines the economics of growth factors, a kind of signaling molecule whose role is to trigger cell growth. “Growth factors can cause a proliferation not only in the cell that produced it but also in other cells in the vicinity,” the paper says. In multicellular organisms, growth is actively regulated by cells acting together, using molecular signals to control cell division, the paper says. The case of cancer, it is these signaling pathways that are altered, or taken over by cancerous cells. And the authors of the paper develop a mathematical model, where the relative benefits and the cost to a cell that generates a signal are compared, to estimate the chances that a mutant cell may be end up becoming cancerous.

The normal cell has evolved to send out signals that would cause proliferation of other cells, altruistically, or even if the signal were sent at a high cost to itself, the paper says. The cancer cell, on the other hand, adapts to use the signals competitively, that would result in advantage to itself. Hence, for the organism to resist cancer, the signaling mechanism used should affect the source cell and other cells, but at little cost to the source cell.

The mathematical model takes a case of a cell mutation that results in the increase in a resource-consuming export of a growth-inducing molecule. There would hence be a rise in the possibility of cell division, and of the death of the source cell. The model was thus a collection of cells, where one cell would be selected to reproduce, depending on its fitness, and another cell would be selected, at random, to die. The objective was to study how the value of receiving a signal and the cost of producing it, as well as the range of a signal, and the distance within which the cell that dies may be replaced by a new cell, were related.

The way the cancerous and normal cell populations progress, leading to the ‘extinction’ or the ‘fixation’ of cancerous cells is then modelled. As it is seen that the cost and the range of signals affect the emergence of cancer, evolutionary control of these factors would act as a regulator of the emergence of cancer. As the evolutionary objectives of the cancerous and the normal cells are opposed, and the cancerous cell needs to reach its objective within its lifetime, normal cells can have native methods that make it difficult for the cancerous aspirant. Keeping cancer wholly out of the reach of mutant cells, however, would come at a high cost. The strategy is hence different in different cells, like blood cells, which are mobile, or tissue cells that stay put.

The study shows framework in which there is a balance of preventing and permitting cancer. If we drew the cancer-preventing methods of the Blue Whale to help humans, it would come at a cost – which may be balanced by the higher cancer-promoting environment that we have come to live in.

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