Scientists are discovering a powerful new way to prevent cancer

IN THE POPULAR imagination, cancer starts with a mutation in the DNA of a normal cell. That mutation allows the cell to multiply uncontrollably, circumventing the body's usual quality-control checks. Eventually, a tumour forms and breakaway cells from it spread to other parts of the body.

But in the past few years scientists have been finding something surprising—so-called cancer-driver mutations are also common in healthy tissue. Such mutations appear in around a quarter of healthy skin cells. When a person is middle aged more than half the surface of the oesophagus and nearly 10% of the lining of the stomach is covered by cells with cancer-driver mutations. These populations of cells have also been confirmed in many other tissues, including the colon, lungs and ovaries.

Why these cells, which are primed to become cancerous, do not grow into tumours is a mystery that scientists are now starting to solve. It seems that cells with faulty DNA can be prevented from growing into full-blown cancers through the activity of healthy cells around them with beneficial mutations in their DNA. Encouraging those healthy cells to grow could become an effective strategy for stopping cancer.

This new understanding of cancer comes from a better understanding of normal tissue growth. As cells divide, each daughter cell is born with a unique set of random genetic mutations. On the outermost layers of organs such as the oesophagus, skin and stomach, those best adapted to their environments push out the rest, which are then shed from the tissue.

Cancerous cells can also be outcompeted. In mice, cells possessing specific mutations have been shown to displace neighbours carrying mutations that are known to increase the risk of cancer, as well as tiny tumours consisting of fewer than 100 cells. This competition for resources may play out over years. Even though cancer-driver mutations often occur early in life, blood samples taken from people as they age have shown that the number of cells with these mutations—including those that progress to cancer—waxes and wanes over time. Boosting cells with beneficial mutations, therefore, may be a way to prevent cancer.

One way to do so may be to learn from these cells' adversaries. A common cancer-driver mutation occurs in PIK3CA, a gene known to regulate cell growth and survival that can, when mutated, cause tissue overgrowth. Phil Jones, a researcher at the Wellcome Sanger Institute in Britain, has been studying PIK3CA. His group discovered that cells with cancer-driving mutations in PIK3CA undergo metabolic changes that help them outcompete non-mutated cells.

In trials involving mice, the results of which were published in August 2024 in Nature Genetics, Dr Jones and his team found that a common diabetes drug called metformin introduced the same metabolic change in non-mutated cells within the oesophagus. By levelling the arms race between unhealthy and healthy cells, metformin was able to halt the growth of cells with PIK3CA mutations. Conversely, when mice were fed a high-fat diet, cells with the troublesome mutation thrived. They were also more numerous in people with obesity, suggesting that interventions targeting the condition could prevent oesophageal cancer.

These results are promising. But putting together a comprehensive list of harmful and beneficial mutations is a challenge. For one thing, the human (or, indeed, murine) body possesses thousands of different cell types, each with a different molecular machinery suited to its role. One mutation on a different gene found to reduce the risk of cancer in the human oesophagus, for example, has been shown in other studies to have no such effect in the skin.

Untangling these complications requires extensive laboratory testing. Fortunately, techniques to do that are improving all the time. Just five years ago, testing the role of a specific gene variant involved breeding mice in which that DNA had been artificially modified—a process that could take years. Researchers nowadays use CRISPR, a gene-editing tool, to modify specific sites on the DNA sequence of a single cell. Dr Jones says that “We can look at 15,000 genes in three months,” of which only the 20 or 30 genes of interest are subjected to further study.

The root of the problem

These discoveries help to shed light on a more profound question: what causes a harmless cell with faulty DNA to develop into a fully-fledged cancerous tumour? External factors are important. Environmental threats such as urban air pollution are known to damage cells and have been linked to higher incidence of cancer. Many chemicals—including some common drinking-water contaminants and ingredients in cosmetics—are also thought to be carcinogenic. But how these carcinogens perform their harmful roles has been more fully understood only recently.

In a study published in 2020 Allan Balmain of the University of California in San Francisco and his colleagues reported that only three of 20 chemicals known or suspected to be human carcinogens actually induced mutations in mice; most appeared instead to promote tumour growth in some other ways. This, says Dr Balmain, suggests that perhaps 80-90% of carcinogens that people are exposed to do not induce mutations.

These non-mutagenic carcinogens instead seem to exploit the body's own immune system. Frequent exposure can lead to chronic inflammation, which in turn encourages cancer-driver cells to develop into full-blown tumours. Inflammation is how the body heals: by dispatching immune cells to the site of an injury, the body can remove irritants, fight infections and trigger the growth of tissue. But when deployed against persistent irritants—such as air-pollution particles in the lungs—inflammation can itself damage the tissue and lead to the formation of tumours. In this sense, tumours have been likened to wounds that never heal.

A study published in Nature in 2023, by a research group led by Charles Swanton of the Francis Crick Institute in London, found strong evidence that urban air pollution causes lung cancers in non-smokers. In mice, air pollution led to inflammation in the lungs, which in turn caused surrounding cells with a mutation characteristic of such cancers to grow and form tumours. The researchers estimated that living for as little as three years in a place where there is lots of air pollution (such as near busy roads in a city like London) may be enough to tip such cells into a tumour-growing phase. Chronic inflammation has also been shown to boost the spread of cells with harmful mutations in response to acid reflux, ultraviolet solar radiation and persistent gut infection with certain bacteria, says Marnix Jansen from University College London.

The discovery that chronic inflammation can provide the impetus for cancers to develop is forcing clinicians to rethink their approach to the disease's prevention. Increasingly researchers think that the best way to stop cancers might be to target the immune system instead of cancerous mutations themselves. Identifying which inflammatory molecule to focus on is the first step. In Dr Swanton's study on air pollution and lung cancer, for example, the researchers discovered that an immune-system protein called interleukin-1ß was enabling the inflammation that stoked tumour development. In mice, drugs that blocked interleukin-1ß suppressed the formation of tumours when the animals were exposed to air pollution.

These discoveries have opened the possibility that new cancer-preventing drugs might help the body better suppress the harmful tendencies of its own immune system. This could be game-changing for those with a high risk of developing cancer. That list includes people with concerning genetic mutations such as faulty BRCA genes, former smokers and people who have already been treated for cancer. Such drugs could also be useful for some people with pre-cancerous tissues, such as polyps in the colon or not-yet-malignant lesions in the breasts or lungs. As lifespans grow and the proportion of people who get cancer continues to rise, the number of potential beneficiaries will grow, too.

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Source: HindustanTimes
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