The development, validation and application of novel preclinical models for the study of Barrett's carcinogenesis
AuthorRead, Matthew David
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-10-07.
© 2019 Matthew David Read
Oesophageal adenocarcinoma is an aggressive malignancy and is associated with extremely poor rates of survival. Its only known precursor is Barrett’s oesophagus, which is a metaplasia that occurs in the lower oesophagus in response to gastro-oesophageal reflux. Despite a number of recent advances, such as the introduction of neoadjuvant therapy and minimally invasive techniques, there has only been a modest improvement in overall survival over the last few decades. One factor that has contributed to this is the limited availability of well- validated, clinically relevant models for research purposes. Therefore, the aim of this thesis, was to develop novel preclinical models for the study of Barrett’s carcinogenesis. Central to this thesis was the optimisation of the patient-derived tumour xenograft model. This is a model in which immunodeficient mice are used as hosts in order to culture pieces of human tumour. Once established, the model provides a perpetual source of tumour tissue. Unfortunately, they have been difficult to establish in oesophageal adenocarcinoma using conventional techniques. Through the use of a novel intramuscular transplantation technique, the efficiency of the model has been greatly improved. Validation has also confirmed that the majority of derived xenografts are representative of the original patient tumour. Importantly, however, validation also confirmed that a subset had undergone lymphomagenic transformation and were no longer representative of the original tumour. Following on from the success of the intramuscular xenograft technique, the model was subsequently used as a source of tissue for the generation of much needed cell lines. Using small pieces of xenograft tissue, rather than single cell suspensions, a robust technique was established for the generation of cell lines. In doing so, a cell line was established that had both metastatic and non-metastatic clones, making it a valuable tool for cancer research. Finally, the intramuscular transplantation technique was also used to successfully culture both normal human oesophageal tissue and metaplastic tissue. Validation of this model also confirmed that the cultured tissue recapitulated the human disease process. In addition to the development and validation of multiple novel models for the study of Barrett’s carcinogenesis, this thesis also begins to explore how these models can be used to investigate clinically significant aspects of disease biology
Keywordsoesophageal cancer; adenocarcinoma; Barrett's oesophagus; preclinical model; patient-derived tumour xenograft; cancer cell lines
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