AbstractColorectal cancer (CRC) continues to be a leading cause of death in the western world and the molecular basis of this disease remains the focus of intensive research. Notch is a highly conserved embryogenic pathway, which is essential for homeostasis in adult tissues and is increasingly implicated in human malignancies, including CRC. Analysis in murine epithelium strongly suggests a central role for these factors in intestinal tumorigenesis; however, the expression and function of N1 in the human colorectal epithelium and CRC remains poorly defined. The aim of this study was to define the expression of N1 in these tissues and to describe possible changes in expression with malignant progression. This study also aimed to model these changes in vitro and to evaluate a functional role for Notch in the human CRC phenotype.
From in vivo analysis, it was found that N1 is expressed in the normal colorectal epithelium and expression is frequently altered in human colorectal tumours; N1 is significantly increased in adenocarcinoma tissues and correlates strongly with malignant progression. These findings were closely reflected using colorectal tumour cell lines in vitro where N1 expression increases with cell cycle progression and tumour de-differentiation. Although a causal role for N1 was not established, these findings suggest a complex and context-dependent basis for the Notch pathway in these tissues. Moreover, this study highlights several important but unappreciated roles for N1 in the non-neoplastic colorectal epithelium. Namely, N1 was found to be expressed in both differentiating cells of the normal colonic crypt and in regions of active tissue repair in inflammatory bowel disease. In summary, the results of this study confirm that altered N1 expression represents important changes in the human colorectal epithelium, including colorectal carcinogenesis, but also that Notch signalling may be responsible for more functions in these tissues than currently described.
|Date of Award||8 Sep 2010|
|Supervisor||Massimo Pignatelli (Supervisor) & J D Qualtrough (Supervisor)|