Dr. Oliver M. Pearce investigates how an antigen derived from red meat and dairy produce is involved in an immune response, which in part facilitates cancer cell creation (tumorigenesis) and carcinoma progression.
Red meat and milk products have been for a long time the subject of controversy among those who debate the health merits and risks of these staples of the Western diet. While these foods supply valuable nutrients like iron, zinc, calcium, and protein, they’ve also been linked to obesity, heart disease, diabetes, and cancer.
Researchers around the globe are working to assess the actual benefits or risks of these foods. Many findings have been for the most part observational based on the eating habits of groups of people and how healthy they are:
- A large population study recently published in the British Journal of Cancer, for instance, followed the diets and health of 61,000 participants over more than a decade. The study found that vegetarians—inclusive of those who eat fish—are 50 percent less likely to develop some types of cancer than people who eat red meat.
- A report compiled by the World Cancer Research Fund and the American Institute for Cancer Research described suggestive evidence that animal fat intake increases the risk of colorectal cancer.
- Another study showed that colon cancer patients who, after having a primary tumor removed, maintained a Western diet that’s high in red and processed meats were three-and-a-half times more likely to have a recurrence than patients who ate higher intakes of fish, poultry, fruits, and vegetables.
Investigations into similar—or even the same—population data, however, contradict these findings:
- A study comparing the mortality of vegetarians and non-vegetarians concluded that causes of death were not significantly different.
- Researchers have also closely analyzed the suggestive evidence from the aforementioned World Cancer Research Fund report. They found that the evidence did not completely support an independent association between eating animal fat and risk of colorectal cancer (although critics of this study point out that it did not single out animal fats derived from red meat only).
With these diametrically opposed conclusions drawn from the same population-based evidence, it is difficult to determine the actual cause of a diet-related human ailment without some more clues.
Ultimately, the correlations these studies suggest or disprove require confirmation by physical evidence. Identifying the mechanisms of cause and effect behind these observations may shed clearer light on their impact on human health. To that end, more researchers have begun to dig deeper to examine the finite ways that these foods affect our bodies.
CRI postdoctoral fellow Oliver Pearce, Ph.D., with his sponsor Ajit Varki, M.D., at the University of California, San Diego, is exploring the link between these foods and higher instances of epithelial cancers, or carcinomas. Specifically, he’s examining the role of a sugar molecule called Neu5Gc and which Dr. Pearce believes is a contributing factor to carcinoma formation and growth.
Why have you singled out the sugar Neu5Gc as a culprit of diet-related cancer?
Dr. Pearce: For some time now red meats and to a lesser extent milk products have been linked to cancer. While many blame mutagens which arise from cooking the meat or ingestion of saturated fats, we learned that red meat and milk products contain high levels of a non-human sugar called Neu5Gc. If we look at our closest evolutionary cousins, the chimpanzees, who are omnivores like us, we noted they don’t seem to be prone to developing the types of cancer that we see in humans. We asked ourselves what was different about them. We noticed two separate but related differences. The first was that chimps, unlike humans, are still able to synthesize Neu5Gc and so naturally display it on their cell surfaces, and the second was that chimps have cell receptors called Siglecs that are responsible for regulating immune responses, while in humans the genes for these receptors have undergone a series of mutations that limit their expression and function.
What’s the connection between Neu5Gc and cancer?
Dr. Pearce: Let’s say you’re a chimp, and you eat a big meal of red meat. Neu5Gc in the meat is going to get taken up into your epithelial cells and presented on their surface. But because Neu5Gc is a natural part of epithelial cell surface anyway there is no adverse immunological response. Now, humans no longer make Neu5Gc. We used to, but approximately 2 to 3 million years ago our ancestors lost the ability to make it. However all the cellular machinery is still present to process this sugar as if it were natural. So when we eat red meat, Neu5Gc still gets picked up by our epithelial cells and presented on their surface, but our immune system recognizes it as foreign and therefore dangerous.
What does the immune system do then?
Dr. Pearce: We have two separate but related theories about this, and that’s what my research aims to answer. The first theory is that when the immune system recognizes the Neu5Gc as “non-human”—when antibodies to the sugar, which all humans have and which are circulating in our body all the time, encounters this non-human sugar on an epithelial cell—it signals danger to the rest of the immune system. We have shown that this results in inflammation—this is what happens when you have an infection and you see red swelling at the site. It’s an influx of immune cells charging in to get rid of whatever needs clearing out. But in this case, the cellular chemicals floating around in an acute inflammatory environment can lead to disruptions in normal cell activity in the surrounding epithelia, and this is what can increase the risk of cancer over time.
What’s your other theory?
Dr. Pearce: The other theory is complementary. We think the relative lack of Siglec receptors on our immune cells results in an over-response to the presence of Neu5Gc leading to a state of chronic inflammation—a long-term immune response against epithelial cells that bear Neu5Gc. Such chronic inflammation can become the perfect environment for tumorigenesis and the cultivation of tumor growth. The receptors (Siglecs) we relatively lack would, if we had them, help to regulate the immune response so that it’s not too strong or prolonged indefinitely. Without them, our immune system maintains a state of constant anti-Neu5Gc activity. In a sense, the human immune system seems to have evolved to be “hyperactive” which for the most part is probably a good thing, but in cases like this it aggravates the condition.
How are you going to carry out your study?
Dr. Pearce: I’m using an interdisciplinary approach that draws upon synthetic organic chemistry, glycobiology, and immunology to mimic Neu5Gc-related immune responses in a transgenic mouse model, and will study the immune mechanisms that are put into action in the presence of Neu5Gc especially from the point of view of tumor progression.
What other implications do you see for this research?
Dr. Pearce: There are two overarching implications that I see. The first will likely define a mechanism by which cancers can arise as a direct result of our diet. This offers us as individuals the chance to make an informed decision on what foods we eat. As a result of understanding why these cancers arise the second implication will be that we will learn how to go about better treating them. This could be particularly useful for patients who have recently had a cancer diagnosed or removed. Here we hope our findings could be used to diminish the chances of the cancer progressing, or in the case where the cancer has been removed, its chance of coming back.
Should people make changes to their diets to minimize their cancer risk?
Dr. Pearce: There are many factors that lead to cancer development, and there are many different types of cancer as well. Should people completely stop eating red meat and only eat poultry and fish? I don’t think it’s going to come to that. Cancer is very much a lottery, but we know already that there are things we can do to decrease the odds of getting it, such as not smoking or reducing the time spent in direct sunlight. In the same way I think our diets need to be thought about carefully, and this research proposes to help people make informed decisions based on the best information we have. I think where this work could be really useful is for helping people who have already had cancer, or have a family history of cancer risk to tailor their diet to significantly improve their chances of remaining cancer free.
How did you become interested in immunology research?
Dr. Pearce: I think my interest in immunology really arose when I was working with viruses to earn my Ph.D. with professors Ben Davis and Len Seymour at Oxford University, UK. I got a whole set of data which didn’t make a lot of sense and it looked like it could be due to perhaps immunological responses, but I realized that I didn’t have training in immunology. So I decided to work in a lab with a focus in immunology for my postdoctoral fellowship.
In particular, my training is in carbohydrates and I went into that because I think that carbohydrates and the role sugars have in biological systems are really important. There is an awful lot of information stored within each sugar molecule. It is also an area a lot of scientists shy away from because it’s seen as being very complicated. My sponsor, Dr. Varki, has been a real pioneer in the field, so it’s been a really wonderful opportunity to work with him and learn a little more about the immunology behind glycobiology.
Why is the CRI fellowship award valuable to you?
Dr. Pearce: The fellowship gives me an opportunity to talk with leaders and experts in immunology. It gives me a chance to meet other academics who are working in the field and get their thinking on what is important and their understanding of these immunological responses that we have. As a chemist looking at immunology, I’ve discovered that the more I read and learn, the more I realize how little I know about it. It’s incredibly complicated to say the least, but very fascinating.
UPDATE [April 20, 2021]: Dr. Oliver is now a lecturer and group leader at Barts Cancer Institute in London. His research is focused on the tumor microenvironment.
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