Biological Characteristics of Gastroesophageal Junction Adenocarcinomas and their Clinical Correlates

Abstract

Gastroesophageal junction adenocarcinomas (GEJA) have increased in incidence in the Western world over the last 50 years, a trend largely attributed to lifestyle factors including obesity and gastroesophageal reflux disease. Their prognosis is poor, and treatment is often complicated by resistance to conventional anti-cancer therapies. Current drug therapies and management strategies used in GEJA have been largely inferred from studies looking at gastric and oesophageal adenocarcinomas, however, a growing school of thought exists which believes that GEJAs have a distinct molecular profile. Investigation of the molecular biology of these tumours may therefore provide us with a novel target for drug therapies, in addition to potential prognostic biomarkers for use in the clinical setting.

Cancer stem cells (CSC) have been extensively investigated across a range of solid organ and haematological malignancies due to their known role in tumorigenesis, invasion, metastasis and drug resistance, yet little is known about their role in GEJA. This thesis investigates the presence of CSC-like cells in GEJA by analysis of the expression patterns of mRNAs, miRNAs and proteins which have previously been described as CSC markers. Molecular markers of EMT were additionally investigated using the same techniques due to the known role of EMT in the regulation of CSCs. This expression data was analysed to seek a significant molecular expression pattern that may be of use in identification, prognostication and/or treatment of aggressive disease.

Chapter 1 presents a background on GEJA, with particular emphasis on advances in tumour classification and drug therapies currently used in the treatment of this disease. Chapter 2 describes the lab techniques used throughout this work, including quantitative real time PCR and immunohistochemical analysis of tissue microarrays. Chapter 3 presents the expression data for each mRNA, miRNA and protein analysed in this study and correlates each individual marker with patient-specific clinical outcomes. Chapter 4 describes the clinical utility of a predictive model based upon the combined expression data from the previous chapter. This chapter additionally interrogates the mRNA and miRNA expression data to determine the signalling pathways involved in the regulation of CSC-like cells in GEJA. Finally, chapter 5 discusses the significance of these findings in the context of the current literature.