How pro-inflammatory diets may create the right recipe for cancer

Abstract

Over the past few decades, the phrase heart-healthy diet has become ubiquitous in public health messages urging people to reduce their sodium and saturated fat intake to help to prevent heart disease. Although the science behind a cancer-conscious diet is not as clear-cut, research has identified some risk-lowering foods such as plant-based proteins and more dangerous foods such as processed meats.

Ongoing studies have investigated a range of potential oncogenic mechanisms. For many foods and food additives linked to cancer, however, “a common underlying mechanistic theme seems to be inflammation,” says Lorne Hofseth, PhD, professor and associate dean for research in the College of Pharmacy at the University of South Carolina in Columbia. Accordingly, more scientists are keying in on foods and additives that may either promote or resolve inflammation.

In one recent study, researchers conducted an extensive analysis of the lipidome, or the entire collection of lipid molecules, in tissue samples from 81 colorectal cancer tumors.¹ Compared to samples from healthy volunteers, the tumor samples revealed a significant pro-inflammatory signature that included multiple products of arachidonic acid, an omega-6 fatty acid that the body can derive from a separate omega-6 fatty acid called linoleic acid.

Conversely, the tumor samples rev-ealed a relative dearth of inflammation-quenching molecules. “Long story short, we think cancer, colon cancer in particular, is a chronic inflammatory disease,” says senior author Timothy Yeatman, MD, FACS, professor of surgery at the University of South Florida and associate center director for translational research and innovation at the Tampa General Hospital Cancer Institute. That inflammation, in turn, may cause immunosuppression that aids the development of tumor cells.

Dr Yeatman and his colleagues support the long-standing idea that cancer is like a “chronically inflamed, poorly healing wound.” Under that hypothesis, cancer is not only a genetic disease marked by mutations in tumor suppressor genes but also a metabolic one in which chronic inflammation and insufficient immune surveillance allow mutation-harboring cells to gain a critical foothold.

What is the link to diet? Multiple studies have characterized Western diets, such as those in the United States, as low in fiber but high in fat—especially in omega-6 fatty acids, which predominate in common food ingredients such as soybean, sunflower, safflower, corn, and other seed oils. Although omega-6, like its omega-3 counterpart, is considered an essential fatty acid, Dr Yeatman says that the cancer connection may be due to a wild overabundance of the former compared to the latter in what we eat. “Consequently, our ratios of omega-6 to omega-3 are out of whack,” he says. “They should be 1:1 ideally, and now people are averaging 25:1.”

A big contributor to the dramatic rise in levels of omega-6 fatty acids in body fat since the 1960s, he maintains, has been the soaring use of cheap, mass-produced seed oils, which are now ubiquitous in highly processed foods. “My contention is that these things aren’t by nature bad. But if you eat them every day in everything you eat, too much of a good thing becomes a really bad thing,” he says.

In agreement with his contention, a recent study of more than 85,000 people in the long-term UK Biobank biomedical database found that a higher ratio of circulating omega-6 to omega-3 levels was strongly associated with all-cause, cancer, and cardiovascular mortality.²

In a separate 2022 study, researchers linked high consumption of ultra-processed foods—ones that are usually high in added sugar, fat, refined starch, and additives such as dyes and preservatives—to an increased risk of colorectal cancer.³ Dr Hofseth is studying the potential contributions of nine synthetic food dyes still used in the United States. Most of these dyes and other ingredients in ultra-processed foods are xenobiotics, he says, meaning that they are foreign to the body. “What do things that are foreign to the body do? They tickle the inflammatory machinery,” he says. Over a prolonged period of time, the “simmering inflammation” they promote may disrupt the body’s cancer-prevention machinery and other critical mechanisms.

In January, the US Food and Drug Administration officially banned the cherry-red colorant known as Red 3 dye in food and pharmaceutical products, based on animal studies that linked the synthetic compound to adenocarcinomas in the thyroid gland, albeit only in male rats. To better understand the potential health effects of the most widely used synthetic dye, Red 40, Dr Hofseth and his colleagues are planning to test its impact on lab-grown human organoids.

On their own, experts caution, most food and food additives probably do not cause cancer directly. Instead, Dr Yeatman says, the potential association with inflammation and its lack of resolution could contribute to oncogenesis in much the same way that red meat might. Here too, the story is far from complete. The lack of distinction between unprocessed grass- and grain-fed beef, for example, could be contributing to relatively weak associations with cancer risk. Under Dr Yeatman’s hypothesis, the association would be far stronger with grain-fed beef (and its far higher omega-6 to omega-3 ratio) than with grass-fed beef.

From a big-picture view of diet, Dr Greenlee says, “The real concern isn’t just individual ingredients but the overall impact of ultra-processed foods on the diet—namely, their displacement of nutrient-dense whole foods, which are essential for good health.”

Our growing understanding of the microbiome has added another wrinkle to investigations of diet–cancer connections. Studies in mice have shown that artificial sweeteners such as sorbitol and erythritol can dramatically alter the microbiome, which in turn plays a key role in regulating the gut’s immune system and associated inflammatory mechanisms. For the additives and ingredients of ultra-processed foods as well as other things that we are ingesting, Dr Yeatman says, an important new question is emerging: “What does that do to the immune system of the gut?”

At a basic level, he and other researchers say that the relatively healthy Mediterranean diet—with its focus on fresh produce, olive oil, whole grains, seafood, nuts, and beans instead of processed foods—could be seen as an anti-inflammatory one. Using the Dietary Inflammatory Index, an algorithm that scores diets according to their inflammatory potential, scientists rated the Mediterranean diet far more favorably than the average Western diet and linked it to a lower risk for lung cancer, especially among smokers.⁴

Marian Neuhouser, PhD, RD, a nutritional epidemiologist and head of the Cancer Prevention Program at the Fred Hutch Cancer Center, agrees that evidence has linked the Mediterranean diet to a lower risk of cancer. Even so, she says, “We’ve not been able to identify precise mechanisms yet.” The diet’s ability to lower inflammation is one possibility, although she notes that olive oil is also rich in antioxidants. “Due to its focus on fruits, vegetables, legumes, and whole grains, the Mediterranean diet is high in many beneficial plant compounds as well as fiber,” she adds.

The focus on inflammation, even if it is only one of many potential cancer-promoting mechanisms, has further led Dr Yeatman and his colleagues to begin promoting the concept of “resolution medicine.” The idea is that some compounds under investigation, such as frankincense and cannabidiol oil, might help to turn on the body’s own inflammation-resolving process. Alternatively, supplements known as specialized pro-resolving mediators—based on molecules normally made by the body—could bypass compromised machinery to help to dampen the chronic inflammation.

In the meantime, Dr Hofseth says that two things are clear: US consumers need more transparency on food labels, and a key part of getting healthier is paying more attention to what we consume. ■