Mazda Jenab is researching compounds identified in various foods, mostly produced from cooking high fat/protein or animal-source foods
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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:
Higher dietary and blood AGEs levels are associated with increased CRC risk and unfavourably with CRC survival post-diagnosis; conversely for blood sRAGE.
Objectives:
To investigate:
(a) Whether higher dietary (Nε-carboxymethyllysine [CML]) or circulating protein-bound AGEs (CML; Nε-(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.
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.
Colorectal (bowel) cancer is a leading cancer in terms of incidence and mortality in many world regions. Yet, it is considered to be highly preventable with adoption of healthy lifestyle and dietary habits.
A number of studies have shown that dietary and lifestyle habits that induce obesity and result in higher body insulin levels are associated with increased risk of colorectal cancer.
Recently, a group of compounds termed Advanced Glycation Endproducts (AGEs for short) have been identified in various foods, mostly produced from cooking of high fat/protein or animal-source foods. It has also been shown that the same compounds can be produced within the body, particularly when blood sugar levels are high.
The conditions that induce production of AGEs also induce inflammation and oxidative stress – two processes that have been shown to result in cancer development, as well as development of other chronic diseases such as diabetes. Interestingly, AGEs can themselves also induce further inflammation and oxidative stress, enhancing cancer promotive stresses on the body.
Thus, both AGEs in foods consumed via the diet and AGEs produced within the body can be of consequence for cancer development. However, there is currently very little evidence that higher AGEs intake or AGEs accumulation in the body is associated with colorectal cancer risk.
The main goal of this proposal is to explore whether and to what extent AGEs, either from the diet or measured directly in blood samples, are associated with colorectal cancer risk. This will be accomplished by comparing values observed in study participants who developed colorectal cancer versus those who did not.
In order to provide some mechanistic insight on the role of AGEs, the project will also assess and compare AGEs levels in a small number of cancerous and surrounding normal colon tissues, and corresponding blood samples.
Given the propensity of AGEs to induce processes that are linked to increased colorectal cancer risk, and their high level of intake in Western-type diets, a study is proposed to measure dietary and body AGEs within a prospective cohort study where data and samples are collected from healthy individuals who are then followed-up for development of colorectal cancer.
The proposed study will be conducted within a large cohort of over 520,000 participants from ten Western European countries known as the European Prospective Investigation into Cancer and Nutrition (EPIC). The study has already collected dietary and lifestyle information, along with blood samples.
The role of dietary AGEs in colorectal cancer development will be studied in >4500 cases that have developed within EPIC. The levels of AGEs in blood will be measured in 1500 of these subjects from whom blood samples have been collected and compared to AGEs levels in an equal number of healthy participants (control subjects), also with existing blood samples.
The dietary AGEs will be estimated using an extensive and detailed database that has been jointly developed for this purpose by two of the co-applicants of this application. The blood AGE levels will be measured using state-of-the-art technologies in the laboratory of a third co-applicant.
The data will be analysed using modern statistical methods to determine differences between colorectal cancer cases and controls. In a separate set of subjects, the project will also measure and compare AGEs levels in colon tumours, normal colon tissues and blood. These samples have been collected by the remaining co-applicant.
The design of this study is both robust (based on a prospective cohort; large number of subjects) and efficient (making secondary use of considerable existing data and blood samples already collected).
This study offers a unique opportunity to comprehensively investigate the role of AGEs in colorectal cancer development. The EPIC project is valuable because of its prospective nature and due to its very large size, meaning greater statistical power to observe real associations.
The knowledge gained from this project will contribute directly to a better understanding of the underlying mechanisms of colorectal cancer development and will propose strategies for its prevention.
