Extrinsic lipids are absorbed and accumulate in colorectal cancer

Background Colorectal cancer (CRC) exhibits increased levels of arachidonic acid-derived pro-inflammatory derivatives indicating an uptake of dietary polyunsaturated fatty acids (PUFAs). Objective We aimed to investigate uptake of extrinsic fatty acids (FAs) in tumours and their relevance for CRC lipid metabolism and progression. Design Total FAs were quantified using gas chromatography-mass spectrometry in non-diseased mucosa and tumour tissue from patients with CRC of a discovery cohort (n=152), validated in an independent cohort (n=28) and associated with clinical, genomic and microbiome data. The genetic mouse tumour model Apc 1638N was used to track the flux of stable isotope-labelled FAs in tumours from the intestinal lumen. The relationship between FA uptake and tumour progression was investigated in 2D and 3D cell models. Results Extrinsic long chain PUFAs, including arachidonic acid, accumulate in CRC, particularly in right-sided tumours, and in tumours of Apc 1638N mice. The CRC-specific FA profiles were independent of sex, molecular subtypes, early-disease or late-disease onset. The absorption of FAs from the intestinal lumen in tumours was confirmed in specific pathogen-free Apc 1638N mice. In the absence of the microbiome, in germ-free Apc 1638N mice, fewer tumours were developed, and survival was increased. Inhibition of FA import or β-oxidation reduces cancer cell proliferation. Conclusion Extrinsic FAs accumulate in CRC, verifying a central role of arachidonic acid-derived inflammatory mediators, but also suggesting a relevance of dietary FAs for cancer cell proliferation. It will be intriguing to explore to what extent targeting this flux pathway together with the interrelated microbiome opens new therapeutic avenues for CRC in humans.