(View plain language abstract)
Colorectal cancer (CRC) 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 CRC. 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 CRC invasion/metastasis.
Conversely, soluble RAGE (sRAGE) is considered to be anti-inflammatory, and hence CRC 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 type2 diabetes.
It has been suggested that excessive AGEs formation in diabetics may be part of the underlying molecular mechanism linking type2 diabetes with CRC. Also, lower circulating soluble RAGE levels have been associated with increased risk of adenoma and CRC in a cohort of Finnish male smokers. Yet, very little other prospective data currently exists on the potential association of AGEs and sRAGE with CRC.
Furthermore, no studies to date have assessed whether any observed associations between AGEs and risk of CRC 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.
Hypothesis and objectives
Higher dietary and blood AGEs levels are associated with increased CRC risk and unfavourably with CRC survival post-diagnosis; conversely for blood sRAGE.
(a) Whether higher dietary (NÎµ-carboxymethyllysine [CML]) or circulating protein-bound AGEs (CML; NÎµ-(1-carboxyethyl)lysine [CEL]) and sRAGE are related to CRC risk or survival.
(b) To what extent any observed associations of circulating measures of AGEs and sRAGE are mediated by inflammation and oxidative stress.
In order to provide some mechanistic insight on the role of AGEs, the project will also assess and compare AGEs levels in a separate series of cancerous and surrounding normal colon tissues, and corresponding blood samples. An exploratory objective is to assess the influence of variation in RAGE and relevant genes.
Settings and methods
This project is based on EPIC, a large prospective study (>520,000 participants; 23 centres; 10 countries) with ready availability of biological samples and detailed dietary/lifestyle information, all collected prior to cancer diagnosis.
The project will first incorporate an existing and detailed database (>550 foods; R. Sinha/L. Jiao/C. Schalkwijk, co-applicants) of dietary AGEs levels into the EPIC database. The association of these with CRC risk/survival will be assessed on the whole cohort (>4500cases) using relevant statistical methodology.
In a matched nested case-control subset (1500 cases), blood AGEs/sRAGE levels will be measured using state-of-the-art UPLC-MS/MS and their CRC associations assessed. Secondary use will be made of existing genetic and biomarker data.
The project is sufficiently sized for appropriate statistical power for the main stated objectives.
This study will add to the existing preliminary knowledge on the role of dietary and circulating AGEs exposure in CRC etiology.
A better and more refined understanding of the molecular and genetic mechanisms of colorectal carcinogenesis will enable targeted and more effective public health advice and policies towards the CRC prevention, along with insight into specific dietary and lifestyle changes for limiting AGE exposure.
Because this study will also explore survival of CRC post diagnosis, its findings will also provide insight into recommendations for CRC survivors.