Cancer could be a seed, and unknown factors might just be nurturing it
Scientists are faced with a mysterious rise in certain types of cancers, and research points to what some are calling ‘dark carcinogens’ which work in little understood ways.
By Sneha Uplekar
Illustration by - Sneha Uplekar
At its heart, cancer is a genetic disease – a result of mutations in the DNA caused by chemicals called carcinogens, which trigger cells to grow out of control and form tumours. It is widely known today that tobacco smoke contains a mixture of at least 70 known carcinogens with a direct causal link to various cancers. How exactly was this link discovered? Through epidemiological studies, that is by studying the incidence of cancer in smokers, and experimental studies which observed the effects of exposing animals like mice to tobacco smoke. The third way, developed by American biochemist Bruce Ames in the 1970s, is the so called Ames test, which works by exposing bacterial cells to suspected carcinogens and studying the mutations they cause. In all three ways, the suspected carcinogen is expected to cause mutations in cell DNA which then trigger the growth of tumours.
But this very logic is now being challenged. Scientists are now having to deal with a new world of cancer triggers. The puzzling and as yet unexplained rise of certain types of cancers in people thought to be at low risk, has raised questions about why some carcinogens might be hidden away and missed by traditional methods of detection, and whether our current understanding of what carcinogens are might need to be re-examined.
Colorectal cancer was once seen to be prevalent among over 60s, but is now the leading cause of death caused by cancer in men under 50 and second leading cause of cancer death in younger women in America. According to the 2023 American Cancer Society report, rate of new colorectal cancer cases among Americans under 55 years, rose from 11 percent of the total number of cases in 1995, to one fifth of total number of cases in 2019. In Europe too, incidence rates among adults aged 20 to 49 years are rising. It’s also seen that cancer in younger people tends to be much more aggressive. One reason for this could be that screening tests for colorectal cancer might be considered by older populations, leaving the cancer in younger people to go undetected until it’s too late.
The precise cause, or causes, of this peculiar rise in cancer among younger populations is unclear, although the body of research is growing rapidly. There is a clear link between obesity and colorectal cancer. Gut microbiota, the intricate network of microbes that dwell in the human digestive system, seem to play a role, and a diet high in ultra processed foods has been linked to gastrointestinal cancers like colorectal cancer in younger people. Exposure to toxic substances like phthalates can also trigger the growth of colorectal and some other cancers. Phthalates are chemicals used, among other things, to make plastics more durable, and can be found in numerous everyday goods, from shampoos, garden hoses, to vinyl flooring.
Predictive models, which make projections about future rates based on worldwide cancer incidence data, anticipate that early onset cancers will rise by 30% from 2019 to 2040. Yet, the number of human-made chemicals which are considered to be carcinogens is surprisingly small. This points to an obvious conclusion, that traditional methods of testing for carcinogenic chemicals, or the definition of what a carcinogen is, must be falling short. Dr Siddhartha Mukherjee, professor of medicine at Columbia University and author of the Pulitzer Prize winning book, Emperor of All Maladies: A Biography of Cancer, refers to these hidden triggers of cancer as the ‘dark matter’ of carcinogens.
A recent groundbreaking study, published in Nature last year, looked at the effects of air pollution on rates of lung cancer. Professor Charles Swanton of the Francis Crick Institute and his team, along with collaborators from across the world, wanted to find out how air pollution is linked to lung cancer in people who have never smoked. The effects of exposure to PM2.5, tiny particulate matter 1/28th the width of a human hair, and which is prevalent in polluted air, were examined in data from over 400,000 people. The effects of PM2.5 on mice were also studied. What they found was not that air pollution caused cells to mutate and turn cancerous, but something far more surprising. Professor Swanton, while speaking to the BBC, said the breakthrough marked a "new era” in our understanding of cancer.
Picture, if you will, a macrophage, a warrior white blood cell whose job it is to protect the body. It plays a key role in defending the body. And it does this by consuming anything it perceives to be a threat through a process called phagocytosis. This can include potential toxins, bacteria, dead cells, and particulate matter in the lungs. But if it fails to do its job of eliminating the threat, it sends out a chemical alarm called interleukin-1-beta, an SOS call signalling that something is very wrong. The body then sends reinforcements of more immune cells and creates an inflammatory response to fight off the threat.
What was already known before, but which the 2023 Nature study confirmed, was that our bodies can already contain cells which have pre-existing mutations, but they do not behave like cancer. But more significantly, it shed light on the precise mechanism which wakes up these sleeping mutant cells – inflammation.
The release of inter beta creates an inflammatory response, which inadvertently activates pre-existing mutated cells. Contrary to traditional understanding that carcinogens are mutagens, PM2.5 is not responsible for causing mutations, but for waking up dormant mutated cells and causing them to turn cancerous.
As Dr Siddhartha Mukherjee put it on an interview with Science Friday, “this mechanism creates the soil in which the seedof the cancer cell can thrive and come into its own. Inflammation produces the conducive environment in which pre-existing cancer cells can grow.”
That inflammation plays a role in the growth of tumours is not new knowledge. Almost 8 decades ago in 1947, Berenblum and Shubik, two researchers based in the Dunn School of Pathology in Oxford, found that mice exposed to a particular carcinogen and subsequently painted with croton oil, which is an inflammatory agent, developed more tumours than those mice that were exposed to the carcinogenic chemical, but not painted with croton oil. This helped them confirm earlier postulations that inflammation can encourage tumours to form. “This is not new knowledge, but it’s been largely ignored for so many decades.” said Dr Lim, one of the co-authors of the study.
A word of caution here. The internet is teeming with any number of videos featuring self-proclaimed health experts warning about the myriad causes of ‘inflammation,’ from childhood stress, to trauma, to cow’s milk, and blaming it for every ailment. But scientific evidence points to the specific type of inflammation, mediated by macrophages, and triggered by interleukin-1-beta.
“Some sorts of stress are linked with causing inflammation in the body, but that does not automatically translate into a proven link between stress and cancer. As ever with science, it becomes critical to tease out the correct meaning and not conflate processes and ideas which ought not to be conflated.” Dr Mukherjee said while speaking to Science Friday.
Understanding of cancer triggered by inflammation is still in its infancy, but may well apply to other cancers caused by exposure to different environmental factors. “People who are not smokers were developing lung cancer, so it was very important to find out why. And pollution is just one example. There will be other examples of inflammatory triggers for cancer” Dr Lim said.
Instead of looking for mutagens, which are chemicals that damage and mutate DNA, researchers could also turn their attention to finding macrophage triggers. It’s still very early days, but future treatments might focus on preventative mechanisms. Recently, drug trial for an interleukin-1-beta inhibitor for cardiovascular disease, stumbled upon another use by sheer chance, cutting the risk for lung cancer.
World Health Organization (WHO) data shows that more than 99% of the world’s populations breathes air polluted far beyond WHO guidelines. We live in an increasingly polluted world, and such inflammatory triggers could be lurking all around us, in the air, water, modern diets, in environments until now thought to be innocuous because we’ve been looking at them through the wrong lens. Finding other human-made triggers for cancer will help strengthen the cause for cleaning up our air, water, soil and diets sooner rather than later.
But on a more optimistic note, we also live in the age of increasingly more capable and powerful technology. Researchers can now have access to vast amounts of epidemiological data, as well harness the immense processing power of AI technology. When combined together, these can throw common factors between environments, populations, and incidence of cancer into sharp relief, all at a previously impossible scale.
The stakes are obviously high, and cancer is a formidable enemy, but as science increasingly expands its understanding of cancer as a dormant seed, we are faced with urgent questions about modern life, and how it may be nurturing this seed.