Award Title: Investigating the impact of adiposity-redox defence interaction on redox homeostasis and inflammatory and cancer-related pathways in human colonocytes
Funder: The Academy of Medical Sciences

Abstract: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and numbers continue to rise. CRC is a complex, multifactorial and multistage disease. Notably, abdominal/visceral fat is a major risk factor for obesity-related diseases and, in particular, cancer. Adipose tissue excess promotes changes in redox homeostasis and inflammation, modifying adipokines and reactive oxygen species (ROS) production/secretion. As such, low-grade inflammation promotes adverse metabolism, affecting homeostasis of redox systems and promoting modification in cell metabolism and signalling cascades at the level of colonocytes. Systematic oxidative stress and inflammation are, therefore, closely interlinked in obesity, but the effect of oxidative stress on colonocytes and its contribution to CRC pathogenesis is not fully understood. Although the body has mechanisms to prevent initial changes related to inflammation and oxidative stress, this redox homeostasis is compromised in excessive weight, and antioxidant defences reduced. Moreover, consumption of essential micronutrients is reduced in obese individuals, leading to malnutrition. Low selenium (Se) intake has been associated with increased body fat and modulation of redox status and inflammation in adiposity and with increased CRC susceptibility. Considering the interplay between adiposity, inflammation, oxidative stress and cell signalling, and in view of relatively low Se status in obese individuals, this project aims to i) assess the impact of adiposity on coloncytes’ metabolic and cell signalling pathways, inflammation and oxidative stress; ii) characterise the effect of modulating antioxidant defences, via Se supplementation, on the interplay between adipocytes and colon cells. A novel approach to co-culture adipocytes (from lean or obese individuals) with colon cells will be used to explore how soluble factors present in adipocytes’ microenvironment affect colonocytes homeostasis and this cross-talk influences oxidative stress, inflammatory and cancer-related pathways. This system will allow to i) understand how oxidative stress and inflammation in adipocytes from obese, compared to adipocytes from lean individuals, may affect inflammation, oxidative stress, antioxidant defences’ markers and cellular bioenergetics in colonocytes and induce activation of cancer-related pathways; ii) identify how Se supplementation may regulate such biomarkers in colonocytes. This proof-of-principle work will provide evidence, in an in-vitro system, of the molecular mechanisms by which oxidative stress/inflammation levels within adipocytes may be regulated by Se and colon epithelial cells’ homeostasis maintained. By providing a strong mechanistic understanding of the molecular links, it will offer unrivalled opportunities to identify potential new therapeutic targets and inform multinational intervention studies, which will define nutritional recommendations for optimal health and lead to future preventive

Lay Abstract: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related death in people. Increased body fat (obesity and overweight) have been reported as one of the main factors responsible for the rise in CRC cases. For this reason, a major focus for research, as well as public health policy, is to understand the mechanisms by which obesity impacts on cancer development and how these mechanisms can be altered to prevent or treat this condition. Excessive body weight promotes changes in the body that make it more susceptible to signals (e.g. inflammation and oxidative stress) that impair the antioxidant defences of the cells, especially in the colon. In addition, obese individuals usually have reduced fruit and vegetable intake consumption and consequently low intake of micronutrients important for optimal health and regulation of antioxidant defences, such as the micronutrient Selenium (Se). This project aims, therefore, to investigate the impact of adiposity on cell metabolism, inflammation and oxidative stress in the colon. An in-vitro system comprising of cells from fat and colon tissue cultured together will be used to identify the mechanisms involved and to define the role of Se in modulating such pathways. By providing a strong understanding of the molecular links between oxidative stress, inflammation in colon epithelial cells associated with obesity and carcinogenesis, and by identifying key biomarkers related to antioxidant defences, this study will offer a great opportunity to define potential new targets and develop, in the future, preventive and therapeutic strategies.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM