role of p53 and its homologues in paediatric neoplasms.
Published: 2004
Language: eng
Number of pages: 216
Description: p53 is the most commonly mutated gene in human cancers with over 50% of tumours harbouring a mutant allele. Acquisition of a  p53 mutation may occur early or late in the development of the cancer and may or may not be a critical rate-determining step. Nevertheless, expression of dysfunctional p53 is often associated with more aggressive tumour biology that is resistant to conventional therapies. The consequences of inheriting mutant p53 allele also illustrate its importance in tumorigenesis. Inheritance of a mutant p53 allele is associated with the Li-Fraumeni Syndrome (LFS), a familial cancer syndrome in which mutant gene carriers are prone to developing a variety of tumours at a young age. The goal of the studies presented in this thesis was to explore novel roles for p53. To this end, we studied the potential therapeutic effects of  p53 gene transfer in paediatric tumours, the oncogenic effects of  p53 mutations in the stromal milieu of paediatric cancers and the p53 homologues (p63 and p73) as potential tumour suppressors.The first section of this thesis is a discussion of p53 and paediatric cancers and provides a rationale for our studies. Section 2 provides the background information necessary to understand the studies and their proper context. The subsequent sections are presented as manuscripts as they were or will be prepared for publication. Section 3 deals with the topic of p53  gene therapy. The studies present pre-clinical in vitro  data to suggest that adenovirus-mediated p53 gene transfer could represent a novel therapeutic approach in treating paediatric sarcomas including osteosarcoma (OS), rhabdomyosarcoma and Ewing's sarcoma, especially the more aggressive forms that are drug-resistant and do not respond to conventional therapy. Section 4 deals with the topic of the oncogenic potential of p53 mutations in the stromal cells of bone marrow in acute lymphoblastic leukaemia. Changes in gene expression in the tumour microenvironment are important in determining the malignant cell's ability to proliferate, invade local tissue and metastasise. Our studies indicate that p53  mutations can occur in the stroma of bone marrow to create a more hospitable environment for the leukaemic blast allowing for increased blast proliferation through the secretion of cytokines including vascular endothelial growth factor (VEGF). Finally, section 5 describes the molecular analysis of the p53 homologues p63 and p73, in US cell lines. We hypothesised that alterations of these genes might explain the cancer phenotype in LFS cases harbouring wild-type p53. Our results indicate that the p53 homologues are not mutated in LFS cell lines and are not likely to be important in the pathogenesis of the disease. Our results are consistent with the findings of other groups that demonstrated the low mutation frequency of these genes and their importance in developmental biology as opposed to being tumour suppressors.Taken together, these studies represent a significant contribution to the p53 field and provide new insight into translational research opportunities in the basic and clinical sciences.
Notes: Adviser:  David Malkin.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4987.