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Title: Regulation of tumour growth and apoptosis by oncogenes and papillomaviruses
Author: Arends, Mark J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1992
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The role of HPV genomes in human cervical neoplasia was re-examined using a new, sensitive PCR-based assay. This demonstrated increasing HPV prevalence with increasing grade of histological abnormality in cervical neoplasia. In contrast, HPV was not observed in histologically normal epithelium from a control group of women defined without reference to attendance at gynaecological or sexually transmitted disease clinics. HPV 16 was associated more with squamous cell carcinomas, and HPV 18 with cancers showing glandular differentiation - the histological type with a poorer prognosis. HPV 18 had a higher cancer/CIN prevalence ratio than HPV 16 indicative of a more rapid transition from CIN to carcinoma. Thus, HPV 18 appeared to be a more aggressive type than HPV 16. A rodent fibroblast model was developed to investigate the effects of HPVs and the myc and ras oncogenes on tumour cell apoptosis and growth rate. These genes were introduced into immortalised fibroblasts, which were studied both in vitro and in vivo. Regardless of the introduced genes, fibroblast proliferation in vitro differed little between the resulting cells lines. In contrast, the rates of cell death (which was uniformly effected by apoptosis) differed widely. Each tumour cell line had a characteristic rate of apoptosis, which determined large differences between the lines in their rates of population expansion in vitro. The tumours produced by subcutaneous injection of these cells into immune suppressed mice also showed large differences in size, which demonstrated a consistent relationship to the relative frequencies of mitosis and apoptosis. Thus, apoptosis appeared to be a major determinant of tumour growth in vitro and in vivo. The ratio of apoptosis to mitosis appeared to be characterised by the genes inserted into these cells. The c-myc oncogene and high risk HPV genomes stimulated tumour cell apoptosis. HPV 18 was associated with lower levels of tumour cell apoptosis than HPV 16. In contrast, the activated ras oncogene suppressed apoptosis, either alone or in combination with the other genes, contributing to the faster growth of ras transfected fibroblasts.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available