Sehgal, Vinay; (2019) The development of a novel endoscopic tumour model of oesophageal adenocarcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: The incidence of oesophageal adenocarcinoma (OAC) continues to rise rapidly. There is a need for appropriate animal models of OAC to both improve our understanding of this disease and use in preclinical drug testing. Current animal models of OAC often fail to replicate the native environment within which OAC develops, and those that do require invasive surgical techniques. It was hypothesised that a less invasive and more clinically relevant animal model could be developed by implanting OAC cells into their native environment endoscopically. Such a model would allow the development of rodent endoscopy and simultaneously offer an opportunity to study OAC in a considerably less invasive manner than surgery. The aims of these thesis were to: i. Develop a method of performing upper gastrointestinal endoscopy in rats ii. Develop an approach of implanting tumour cells into the oesophageal submucosa of rats under direct endoscopic guidance iii. Assess the feasibility of growing human OAC cells in the oesophagus of immunodeficient rats after endoscopic implantation of tumour cells. Methods: Preliminary anaesthetic and endoscopic experiments were conducted to help devise a novel technique of performing rodent endoscopy. Two human cancer cell lines (HT29 and OE19) which were stably transfected to express luciferase were endoscopically implanted into the oesophageal submucosa of nude rats. Whole-body bioluminescent imaging (BLI) and endoscopy were performed at regular intervals to provide complimentary data to assess tumour development in animals. Results: A method of performing rodent gastroscopy which required endotracheal intubation to prevent rodent asphyxiation has been developed in this thesis. All implanted cancer cells were detected immediately after injection using BLI. All 3 rats injected with HT29 cells +/- Matrigel grew cancers, 2/3 of which were visible endoscopically. In comparison only 1/4 rats that were implanted with OE19 cells developed a cancer and this required Matrigel. The addition of Phorbol 12-Myristate 13-Acetate (PMA) to Matrigel led to cancers developing in 2/3 animals implanted with OE19 cells. Despite refinement of the injection needle, it was not possible to grow exophytic tumours which invaded the oesophageal lumen in any animal. Conclusion: The work in this thesis presents preliminary data pertaining to the development of a novel orthotopic tumour model for OAC. By utilising rodent gastroscopy, this model replicates the native environment in which OAC grows in a manner that confers less morbidity to animals. These findings support the original hypothesis that a less invasive and more clinically relevant animal models could be obtained by implantation of OAC cells into their native environment. The outcome of this thesis should provide a foundation for further research into developing appropriate animal models to improve our understanding of OAC.

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