Molecular Effects of Aspirin & Metformin on Colonic Epithelium

Overview

Bowel cancer, a significant problem in the United Kingdom (UK) with \~ 41,000 diagnoses and \~ 16,000 deaths annually, has a large preventable component (\~54%). It is, in part, due to energy imbalance within bowel cells as suggested by associated risk factors: high-fat diet, obesity, physical inactivity and type 2 diabetes mellitus. Drugs that decrease bowel cancer risk, like aspirin and metformin, may prevent the disease by mimicking the molecular effects of dietary restriction and exercise. Energy imbalance, through obesity, expands stem cells which may increase bowel cancer. We have shown that aspirin activates an energy molecule, which increases when we exercise, and blocks signalling associated with obesity in bowel cancer. Indeed aspirin in combination with metformin (commonly used in diabetes) has a greater effect on this pathway than either drug alone. To predict which patients may benefit from aspirin and metformin, we need to discover if these drugs may mimic healthy lifestyle changes at a cellular level and which cells are being targeted. This project investigates how aspirin and metformin influence energy molecules in bowel cells to mimic beneficial effects of exercise or dietary restriction. Participants, recruited from Western General Hospital (Edinburgh) colorectal clinics, will have bowel lining and blood samples take initially and then depending on their assigned cohort, after; 24 hours, 7 days, 28 days or a 6-week course of aspirin, metformin or both tablets. Samples will be analysed for energy genes (main outcome). Secondary outcomes will measure effects on quantitative faecal immunochemical tests (qFIT), used to detect blood in the stool, and on gut bacteria. This critical research will inform how aspirin and metformin can be used in specific populations to decrease bowel cancer risk and to develop new drugs to target abnormal energy pathways.

Colorectal cancer (CRC) is eminently preventable, and yet it is the 2nd most common cause of cancer death in the UK. Both population growth and ageing will influence CRC incidence. There is a significant environmental aetiological component, with around 54% being preventable. Modifiable risk factors include obesity, metabolic syndrome, type 2 diabetes mellitus (T2DM), and physical inactivity.Recent data suggests that the rising CRC incidence in young populations is associated with the increase in obesity and T2DM. Hence, there is substantial rationale for developing approaches that define and modify CRC obesity-related risk. Cancer cells have long been observed to reprogramme metabolism to generate substrates for growth. There are multiple molecular mechanisms linking obesity and CRC. Obesity is the commonest cause of insulin resistance and T2DM. Obesity-mediated insulin resistance and inflammation may drive CRC. Obesity increases early CRC precursor lesions of aberrant crypt foci. Bariatric surgery reduces adenomas and decreases CRC risk biomarkers such as proliferation and inflammation markers. High-fat diet (HFD) animal models of obesity and carcinogen-induced CRC show intestinal stem cell expansion. Dietary fatty acids themselves may drive stem cell expansion. Highlighting further complexity, intestinal epithelial insulin receptor deletion attenuates the HFD-induced increase in cholesterol and stem cell messenger ribonucleic acids (mRNAs). Calorie restriction, associated with longevity and reduced cancer incidence, may be mediated through downregulation of nutrient-sensing pathways. Agents that clearly decrease CRC incidence, such as aspirin and metformin (may act as calorie restriction mimetics by influencing nutrient-sensing. The host lab have shown that low-dose aspirin reduces CRC incidence in the Scottish population and that high-energy snacks are associated with CRC risk -strengthening the link between energy, diet and cancer. They also demonstrated that aspirin modulates key nutrient-sensing pathways; aspirin activates AMP-activated protein kinase (AMPK) and inhibits mammalian target of rapamycin (mTOR) signalling in CRC cells, mouse intestine and patients. Furthermore, there was a synergistic effect with aspirin and metformin with respect to AMPK activation and mTOR inhibition in CRC cells. The protective effect of aspirin may be greater in higher body-mass index (BMI) patients. Mendelian randomisation studies strengthen causal links between obesity, hyperlipidaemia, pro-inflammatory fatty acids and CRC risk. This study aims to elucidate the underlying molecular mechanisms of aspirin and metformin with respect to their cancer preventing properties in the colon, thereby identifying potential critical "druggable" targets. The ultimate aim is to predict which patients may benefit from these drugs to prevent CRC.