Talks, Katherine Louise; (2004) The role of hypoxia signalling pathways in tumour biology. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The hypoxia inducible transcription factors HIF-1 and HIF-2 mediate the hypoxic regulation of a number of genes important in embryogenesis, physiological adaptation to hypoxia, angiogenesis and tumourogenesis. The level of the respective a-subunits of the HIF-1 and 2 heterodimers determines the level of protein and transcriptional activity. Angiogenesis is both an important process in tumour development and provides a new therapeutic target. A greater understanding of its role at different stages of tumourogenesis and the identification of biological markers of hypoxia are required to optimise the clinical use of antiangiogenic agents and objectively monitor response. The characterisation of monoclonal antibodies (MoAb), which recognise HIF-l and HIF-2 epitopes in formalin fixed, paraffin embedded material and the human tissue distribution of these proteins is presented. HIF-l and HIF-2 protein was detected in a subset of most common types of cancers. In contrast staining was negative in normal tissue, except in a subset of macrophages, indicating differential activation of HIFs within tumours. A perinecrotic distribution of HIF protein was found in some tumours, consistent with local microenviromental factors influencing expression. In-situ hybridisation studies demonstrated co-localisation of vascular endothelial growth factor (VEGF) mRNA and HIF- protein within a series of necrotic breast carcinomas, indicating functional activity. An unexpected finding was strong HIF-2 expression in a subset of tumour associated macrophages (TAM). The specificity of the TAM reactivity was confirmed using a polyclonal antiserum against HIF-2 . The interaction between tumour and stromal cell components of tumours is important in determining angiogenesis activity. The expression of HIF-l by both tumour and stromal cell components of cases of breast carcinoma was positively associated. Within Hodgkin's disease (HD) and non-Hodgkins lymphoma (NHL) both neoplastic and reactive TAM expressed VEGF. Overall this work adds to the knowledge of HIF expression and presents new information on the role of TAM.

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