Investigating the role of fatty acids and adipose in obesity-linked oesophageal and colorectal cancer

Living with obesity and increased adiposity elevates the risk of developing cancer, including oesophageal adenocarcinoma (OAC) and colorectal cancer (CRC). Diets high in saturated fatty acids (SFA) promote higher adipose tissue inflammation, insulin resistance and metabolic abnormalities compared to monounsaturated fatty acids (MUFA). Furthermore, SFA-rich diets drive adiposity in the visceral adipose tissue (VAT) depots, while diets rich in MUFA support more subcutaneous adipose tissue (SAT) accumulation. However, the comparison between different fatty acid classes within the context of obesity-linked cancer requires further investigation. At the outset of this project, it was apparent that obesity and a high-fat diet increase cancer risk. However, the lack of information about the specific mechanisms that are driven by the different classes of fatty acids and cancer development was evident. Furthermore, the differences that adipose depot location could have on cancer progression required more investigation. Thus, this thesis provides essential insight into how the type of fatty acid and adipose location alter cellular metabolism in non-cancerous and cancerous models of OAC and CRC. This thesis examined the difference between SFA and MUFA in cell models of OAC and CRC to underpin the mechanistic differences the fatty acid classes have depending on the development of the disease. A metaplasia model of Barrett’s Oesophagus and an OAC model showed that SFA, not MUFA, induced more inflammatory, lipid metabolism and mitochondrial reconfiguration related to oncogenic behaviour in the pre-neoplastic stage versus the established OAC model. Models of CRC were utilised to show the tumorigenic model was influenced by SFA to change signalling pathways relating to inflammation and lipid metabolism in comparison to MUFA. VAT versus SAT adipose conditioned media (ACM) treatments highlight the influence of adipose secretome on cellular metabolism was dependent on the type of cancer with more modulation in the metaplasia stage in the OAC disease cascade and alternatively the tumorigenic model in CRC. Overall, this thesis successfully identified different regulatory mechanisms dependent on SFA or MUFA and VAT versus SAT ACM. Specifically, SFA and VAT ACM treatment induced more changes that were in line with oncogenic behaviour compared to MUFA and SAT ACM. Collectively these results present the potential of nutrition to modulate tumorigenesis. Moreover, it highlights the specific timing when nutrition may have the greatest influence on oncogenic cell metabolism. Ultimately, the experiments outlined in this thesis will improve our understanding of how diet may aid conventional therapies utilised in relation to cancer initiation and progression.