Hutchins, Robert R.; (2002) A study of the role of oncogenes and tumour suppressor genes in malignant pancreatico-biliary tumours. Masters thesis (M.S), UCL (University College London).

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Abstract

The molecular understanding of tumour development and progression has advanced considerably with the discovery of oncogenes and tumour suppressor genes. Surgical treatment is the only therapy that offers the potential for cure in hepatopancreatobiliary malignancy. Distinct from other solid tumours, HPB malignancies are unique in that many patients are considered unresectable despite only local, small volume disease. "Curative" resection unfortunately fails in 50% or more of cases. With such poor responses from conventional medical treatments, these tumours are potentially a target for genetic manipulation. The aim of this study was to identify those protein products abnormally expressed in HPB malignancy (by immunohistochemical analysis). In order to narrow down the field of protein products to be investigated, those that are abnormally expressed commonly in foregut tumours were chosen (p53, c-myc, MIB-1, Bcl-2 and c-erbB-2). Given that the embryological derivation of HPB tumours is also foregut, these factors were investigated in this group of neoplasms looking for distinguishing or diagnostic characteristics in expression. The results were compared with expression within pre- invasive, invasive and pre-malignant lesions of the same tissues. No classification based on expression of any of the oncogene products could be used to distinguish the site of tumour origin. Based on comparisons with benign and normal tissue examples, no useful diagnostic differences were discovered between expression of any of the markers. To assess whether expression was a feature of aggressive biological behaviour, comparisons were made for each grade of tumour. Only ampullary lesions had a significant increase in expression of p53 protein with advancing grade of tumour. Confirmed was the suspicion that immunohistochemically-expressed p53 protein is not confined to malignant cells alone. There was a high percentage of expression of c-myc and p53 proteins in all tumour sites, but seemingly no relevance to cancer development. Given this, the second stage of this study was to investigate controlling mechanisms around these proteins and assess whether these dictated the progression of the cell cycle to mitosis or release to differentiation, cell death or DNA repair pathways and thus avoidance of malignant change. In-situ hybridisation techniques were used to assess the expression of mRNA (MDM-2, p21WAF-1, Bax and BCLX1 cDNA probes constructed in-house) in serial sections of ten cholangiocarcinomas and two normal gallbladders. This was compared with expression of p53, MDM-2, p21WAF-1, Bax, c-erbB-2, Bcl-2, MIB-1 and c-myc proteins by immunohistochemistry and cell death (apoptosis) by histopathological assessment and the TUNEL assay. Heterogeneity of expression resulted in no correlation between markers being of any significance or in any pattern of expression within a tumour group compared to normal biliary epithelium. The third stage of the study was to assess whether any protein expression had prognostic significance in cholangiocarcinoma compared to accepted prognostic clinical and pathological criteria by Kaplan-Meier survival analysis. No marker performed usefully in assessing aggressiveness of disease. An incidental finding during this study was that Bcl-2 plays no part in regulating cell survival within the biliary tree. This is distinct from the overwhelming majority of other tissues where Bcl-2 does regulate survival. This role, in the biliary tree, is performed by a Bcl-2-related gene - BclxL. This is now being more formally assessed in further studies as well as the response of cholangiocarcinoma cells to manipulations of these and other cell survival factors.

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