Oesophageal cancer is the ninth most common cancer globally and the sixth leading cause of cancer-related deaths. The reason? The high mortality rates associated with oesophageal cancer are largely due to the late-stage diagnosis and aggressive nature of this type of cancer. Oesophageal adenocarcinoma (OAC) is one of the major forms of oesophageal cancers in western countries. OAC, is often linked to a condition called Barrett’s oesophagus (BO), driven by long-term acid reflux (gastroesophageal reflux disease or GORD). Obesity is another key risk factor. However not everyone with BO and/or obesity develops cancer, which makes early detection incredibly challenging.
One of the key aims of my PhD research project is to find early warning signs. The ‘risk markers’ in the blood that can help identify who is most likely to develop OAC. We are also investigating whether healthy lifestyle changes can reduce these markers in people recovering from gastrointestinal cancers, potentially lowering their chances of cancer reoccurrence.
Listening to the Blood: A Clue in ‘Good’ Cholesterol
One of the biggest challenges in identifying ‘risk markers’ in the blood of patients with Barrett’s oesophagus (BO) or oesophageal adenocarcinoma (OAC) is that blood contains a mix of biological substances—like proteins, fats, and other molecules—released by all the cells in the body. It’s like trying to spot specific messages from the gut in a very ‘muddy’ soup.
To tackle this, I’m working on ways to isolate signals that are coming specifically from the gastrointestinal (GI) tract.
There are several ways that we can attempt to do this but my laboratory is particularly interested in ‘good cholesterol’ or high-density lipoprotein (HDL) particles. You may be familiar with measurements of HDL-cholesterol (HDL-C) in a routine blood test from your doctor’s office – HDL-C is usually measured to screen for your risk of heart disease (low levels of HDL-C indicate higher risk of heart attack).
What Makes HDL So Interesting?
Importantly, for my project, these particles carry over 200 proteins in your blood. While 70% of these particles come from the liver, the remaining 30% come from the GI-tract!! This makes these particles potentially important ‘delivery trucks’ of GI-derived proteins into the blood! We therefore think if we isolate HDL from blood, and separate GI- from liver-containing HDL particles, that we may be able to identify signals coming from the intestinal tract which is very exciting. My job is now to identify the optimal approach to do this and identify new ‘risk’ markers. I hope one day it will become a routine blood test in the clinic for screening patients for OAC.
Let’s take a deeper look into HDL particles and why I am so interested in them!
Cholesterol is a type of fat (lipid) that travels through your bloodstream in little packages called lipoproteins. There are two main types: LDL, often called “bad cholesterol,” and HDL, known as “good cholesterol.”
Cholesterol plays a crucial role in your body—it helps build cell membranes and make hormones. Your liver produces about 80% of the cholesterol you need; the remaining 20% comes from what you eat, such as meat, dairy, and foods high in saturated fat.
Even though cholesterol is essential, having too much of it, especially the kind carried by LDL particles—can lead to heart disease. LDL tends to drop off cholesterol throughout the body, including into artery walls, which can cause blockages. HDL, on the other hand, acts like a clean-up crew, collecting cholesterol and bringing it back to the liver so your body can get rid of it (fun fact: eating fibre helps flush it out more effectively!).
This is why we call LDL “bad” and HDL “good” even though the cholesterol they carry is the same. It’s the direction they travel and what they do with that cholesterol that matters. People with high LDL and low HDL levels are at especially high risk of heart disease.
When it comes to cancer, we still have a lot to learn. But research shows that too much cholesterol inside immune cells can make them more inflammatory. This chronic, low-grade inflammation may increase cancer risk. HDL helps here too. It reduces inflammation by lowering cholesterol inside those immune cells.
And as we’ve seen, HDL isn’t just about cholesterol, it carries a diverse set of proteins, making it a fascinating and important part of my research.
Harnessing the power within HDL particles:
My group has previously shown that the types of proteins attached to HDL particles are adversely changed in some people living with obesity (PwO). More specifically HDL particles, the so-called “good cholesterol” have an increased association of inflammatory proteins, and loss of anti-inflammatory and antioxidant proteins. These effects occurred independent of HDL-C levels – i.e. the proteins on HDL particles were altered in many individuals where HDL-C levels were unchanged. Interestingly, these in HDL protein composition changes aren’t ‘captured’ in traditional measures of HDL-cholesterol.
To explore this further, my group has developed a new blood test that can measure over 100 different proteins on HDL particles. I’m going to use this tool to investigate whether these protein patterns can help us identify individuals at high-risk versus low-risk of OAC.
However, another challenge for my project is to separate HDL that comes from the liver versus the GI tract! These can be marked by a protein called ApoA4, that is thought to be enriched on HDL from the GI tract. I plan to isolate ApoA4 containing HDL particle from the serum and study these specific proteins. I hypothesize that this approach will enable me to identify specific ‘high-risk’ warning signals for OAC, that will enable timely intervention.
Is there any way I can improve the composition of my HDL particles?
There is currently no FDA/CE-approved blood-test that comprehensively measures HDL-proteins – we hope to have a new test that is ready for clinical use in the next 5 years. We therefore have limited information on how to improve HDL composition with much research required in the next few years.
However, we do know a few key points:
- Diets enriched with saturated fats are associated with a more inflammatory state of HDL particles compared to diets enriched with monounsaturated fats.
- Significantly weight-loss post bariatric surgery can restore HDL particles back to a healthy state (reduced inflammatory proteins and increased antioxidants).
- Diets rich with fibre can increase cholesterol elimination from the body to help sustain a healthy cholesterol balance in the body (plant stanols/sterols are also great here to prevent cholesterol reabsorption from the gut).
My research will provide greater insights into how an exercise intervention in high-risk OAC patients modulates HDL-associated proteins which will give further insights into optimal approaches to reduce long-term risk of OAC.
My goal is to develop a simple blood test that can identify people with BO who are most at risk of developing oesophageal cancer — so we can catch it early and save lives!
References:
NAZIR, S., JANKOWSKI, V., BENDER, G., ZEWINGER, S., RYE, K. A. & VAN DER VORST, E. P. C. 2020. Interaction between high-density lipoproteins and inflammation: Function matters more than concentration! Adv Drug Deliv Rev, 159, 94-119.
Image created using BioRender
Author: Pousali Chatterjee, UCD School of Medicine
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