Background
Bowel cancer is a leading cancer in terms of incidence and mortality, and has been identified as one that is highly preventable by dietary/lifestyle changes.
Observations from large prospective cohort studies suggest a compelling role for hyperinsulinemia, hyperglycemia, inflammation and oxidative stress in bowel cancer. These processes induce, and are induced by, Advanced Glycation End-products (AGEs), which can be produced in foods (high fat/protein diets, animal foods; with cooking) or endogenously, with enhanced production in hyperglycemic/oxidative environments.
AGEs are thought to affect carcinogenesis directly and via activation of their receptor (RAGE) resulting in intracellular production of reactive oxygen species, transcription factor activation, and acute/chronic inflammation. Experimental studies show a pro-inflammatory role for RAGE activation in the colon, while clinical studies suggest an involvement in bowel cancer invasion/metastasis.
Conversely, soluble RAGE (sRAGE) is considered to be anti-inflammatory, and hence bowel cancer protective, as it competitively inhibits RAGE-mediated actions. Higher dietary AGEs exposure and/or circulating AGEs levels (reflecting environmental exposures and endogenous production) have been shown to be associated with a number of chronic diseases – especially type 2 diabetes.
It has been suggested that excessive AGEs formation in diabetics may be part of the underlying molecular mechanism linking type 2 diabetes with bowel cancer. Also, lower circulating soluble RAGE levels have been associated with increased risk of adenoma and bowel cancer in a cohort of Finnish male smokers. Yet, very little other prospective data currently exists on the potential association of AGEs and sRAGE with bowel cancer.
Furthermore, no studies to date have assessed whether any observed associations between AGEs and risk of bowel cancer maybe modulated by variation in genes for RAGE or genes known to be involved in inflammatory or oxidative processes, which appear to be central to AGEs function.
Aims and objectives
Our main goal was to assess the association of AGEs from the diet or measured directly in blood samples (along with blood measures of sRAGE) with bowel cancer risk and survival post-diagnosis. This was accomplished by comparing measures in bowel cancer cases versus cancer-free participants. In order to provide some mechanistic insight on the role of AGEs, the project compared AGEs levels in some cancerous, surrounding normal colon tissues and corresponding blood samples.
Settings and methods
This study was conducted within the large EPIC cohort (>520,000 participants, 10 European countries). We developed a database of dietary AGEs exposures from detailed dietary data within the cohort and we measured blood levels of 3 major AGEs and sRAGE using modern techniques in ~1400 bowel cancer cases and an equal number of controls.
We also analysed AGEs levels in matched blood and colon cancer tissues from another study to assess AGEs accumulation in tumour tissues. We conducted statistical analyses on all our collected data. We also assessed the association between AGEs and length of time of survival from bowel cancer after diagnosis.
Results
The results showed that higher sRAGE concentrations were inversely associated with bowel cancer, but this association was only seen in men. We also showed that participants carrying a genetic variant (in the promoter of region of AMAM10) had lower bowel cancer risk.
We found that a higher concentration of AGEs derived from “methylglyoxal” precursor was associated with bowel cancer, but higher levels of AGEs derived from “glyoxal” were not, suggesting a complex relationship between different types of AGEs and cancer risk.
Conclusion
Contrary to our initial hypothesis, the findings suggest an inverse association between dietary AGEs and bowel cancer risk. More research is required to verify these findings and better differentiate the role of dietary AGEs from that of endogenously produced AGEs and their precursor compounds in bowel cancer development.
Impact
The publications resulting from this grant are the first to assess the role of AGEs in bowel cancer based on data from a large, multi-national cohort. These findings shed light on the highly complex role of AGEs in cancer development and identify the potential, unexplored role of AGEs within the body.
Grant publications
- Mao, Ziling, et al. “Prediagnostic Serum Glyceraldehyde‐Derived Advanced Glycation End Products and Mortality among Colorectal Cancer Patients.” International Journal of Cancer, vol. 152, no. 11, 30 Jan. 2023, pp. 2257–2268, https://doi.org/10.1002/ijc.34449.
- Tsilidis, Kostas K., et al. “Dietary Advanced Glycation End-Products and Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.” Nutrients, vol. 13, no. 9, 2021, p. 3132, www.mdpi.com/2072-6643/13/9/3132.
- Karavasiloglou, Niki, et al. “Dietary Intake of Advanced Glycation End Products (AGEs) and Mortality among Individuals with Colorectal Cancer.” Nutrients, vol. 13, no. 12, 2021, p. 4435, www.mdpi.com/2072-6643/13/12/4435.
- Tsilidis, Kostas K., et al. “Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.” Carcinogenesis, vol. 42, no. 5, 2021, pp. 705–712, academic.oup.com/carcin/article/42/5/705.
- Aglago, Elom K, et al. “Soluble Receptor for Advanced Glycation End-Products (SRAGE) and Colorectal Cancer Risk: A Case–Control Study Nested within a European Prospective Cohort.” Cancer Epidemiology Biomarkers & Prevention, vol. 30, no. 1, 20 Oct. 2020, pp. 182–192, https://doi.org/10.1158/1055-9965.epi-20-0855.
