Charlie Swanton: Cancer's Swiss cheese effect
Interview with
The government announced this week that they are formally launching bowel cancer screening for people over 50 across the UK. Many countries also have similar sorts of screening programmes. Their rationale for doing this isn’t just that it’s a good idea to detect cancers early; they’re saying it’s becoming more common in this particular age group. So, at a time when we can do more, detect more, treat more, and know more about these diseases and their causes, why are we seeing some cancers encroaching on age ranges where they were historically much rarer?
Charlie – There are several potential reasons for this, and it’s both intriguing and actionable. One explanation could be the changes in Western diets over the past 60 or 70 years, particularly in the post-war era. Some might suggest this is simply a reflection of increased energy intake, while others propose that ultra-processed foods might be contributing. Other potential causes that have been mooted include greater antibiotic use, changes in the microbiome, and even pollution—potentially microplastics and other pollutants ingested as part of our diet. Right now, there is no clear answer to the underlying cause of this increased prevalence. However, I suspect there’s something very specific to diet.
Why do I say that? If we compare South Korea and Japan and look at the incidence of bowel cancer in the under-50s, it’s increasing in South Korea but not in Japan. The populations are ethnically similar but have quite distinct diets. This suggests that something about the Westernised diet, which is slightly more prevalent in South Korea than Japan, might offer clues about why this disease is increasing in younger age groups.
Chris – What do you think those risk factors, including diet, are doing? How do they translate into cancer—whether it’s lung cancer, bowel cancer, or pancreatic cancer?
Charlie – To answer that, we need to identify the clearest proximal epidemiological risk factor, which we don’t know yet. My suspicion is the Western diet. The next question is: why might that be?
One possibility is how the diet alters the microbiome. We know some gut bacteria can cause or induce mutations in the gut’s mucosa, and these mutations are implicated in the earliest steps of tumour initiation. But I think it’s more complicated than that.
Recent work by Alan Balmain and colleagues at UCSF has shown that most carcinogens causing cancer in humans don’t induce mutations in mouse models, meaning they must cause cancer by other mechanisms—possibly through inflammation.
Chris – But cancer is a genetic disease, isn’t it? If I examine a cancer cell, I find it’s riddled with genetic changes by the time the cancer is well developed. At what stage do these genetic changes occur to make the cell misbehave? Are you suggesting there’s a trigger upstream of the mutations?
Charlie – If you’d asked me five years ago how cancer begins, I’d have said we’ve largely solved this: it starts with mutations in certain genes that provide the cell with a proliferative advantage.
But recent studies challenge this model. Deep sequencing of normal tissue—skin, lung, and liver—has revealed cancer-causing mutations throughout our bodies, including in the eyelids.
Chris – Even in young people?
Charlie – Yes, even in young people, although these mutations become more prevalent with age. For example, the Sanger Institute conducted an elegant study taking multiple biopsies of the eyelid and subjecting them to deep sequencing. They found many mutations traditionally associated with cancer.
Chris – So, the body is full of the genetic hallmarks of cancer all the time, but it doesn’t manifest in even a fraction of people with those changes?
Charlie – Exactly. My colleague James DeGregory at the University of Colorado estimates that a 60-year-old person will have 100 billion cells with mutations commonly associated with cancer. Yet, our lifetime risk of cancer is between one in two and one in three. To give you context, the human body has roughly 30 trillion cells. So, at the cellular level, cancer is incredibly rare, even though 100 billion cells carry these mutations.
What’s happening is that cancer initiation requires a two-step process. Mutations might be necessary but are not sufficient on their own. Instead, a second step is required, often referred to as a promoter step, which can be triggered by chronic tissue inflammation.
For example, air pollution particles taken up by immune cells, like macrophages, can’t be digested. These cells release inflammatory signals that act on stem cells carrying cancer mutations, triggering tumour development.
Chris – So, asbestos exposure is a good analogy here? Asbestos fibres get deep into the lungs, frustrating the immune system, which produces inflammatory signals. If nearby lung cells have random genetic damage, the two factors combine to increase cancer risk?
Charlie – Precisely. Mesothelioma is a prime example of this. The fine asbestos fibres get into the lung and are taken up by macrophages, which release inflammatory signals like interleukin-1 beta. These signals act on cells with mutations—the wrong mutation, in the wrong cell, at the wrong time—resulting in cancer. It’s like a Swiss cheese model, where all the holes line up to cause disease.
Chris – This aligns with findings on drugs like aspirin, doesn’t it? People with colon cancer who take aspirin have a lower chance of recurrence. Does aspirin suppress inflammation, reducing the likelihood of that “one-two punch” Swiss cheese effect?
Charlie – That’s my assumption, though we need more evidence to prove it. But it’s certainly plausible.
Chris – So, should we all take anti-inflammatories to prevent cancer?
Charlie – If only it were that simple! These findings highlight opportunities for intervention. However, we need to identify the key inflammatory regulators where we can intervene. At present, we don’t know what those are. We have some strong clues, and over the next decade, our lab will focus on understanding these nodal regulators of tissue inflammation—essentially, what’s allowing those holes in the Swiss cheese to form.
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