Angiogenesis in human cancer
Angiogenesis is the formation of new vessels from existing vasculature and is essential for tumour growth and metastasis. It is controlled by angiogenic factors secreted by the tumour which regulate the matrix remodelling, endothelial cell (EC) proliferation, and capillary differentiation necessary for establishing a blood supply. This thesis has examined angiogenesis in human tumours. Immunohistochemically highlighted vessels in tumours were quantified using different methods to develop a rapid and objective method for measuring tumour angiogenesis. Significant associations between Chalkley counting, microvessel density, vascular area and perimeter were demonstrated; the Chalkley technique gave independent prognostic information and was suitable for a diagnostic service. Studies on the frequency EC of S-phase showed proliferation (labelling index 2.2%) occurs mostly at the tumour margin suggesting the growth factors controlling ECs are different from those regulating tumour cells and that remodelling the existing vasculature might play a more important role than previously recognised. To investigate further ECtumour matrix interactions, the expression of cell adhesion molecules (CAMs) was examined. CAM expression mirrored that of EC proliferation with preferential expression on endothelium at the tumour periphery: expression of CAMs was also present on neoplastic cells. Thus, acquisition of CAMs by tumour cells together with EC phenotypic modulation might promote angiogenesis and metastasis. The angiogenic factor thymidine phosphorylase (TP) was examined in normal tissues and tumours. Although TP was expressed in ECs there was no correlation between expression in normal or neoplastic tissue and vascularity. Nevertheless, TP was elevated in small low grade tumours, in accordance with TP being chemotactic but non-mitogenic for ECs. A monoclonal antibody to flt-4, a candidate angiogenic factor receptor was generated and characterised. In contrast to the in-situ mRNA expression profile, a restricted pattern of protein expression was observed in normal tissues and variable expression in tumours.