ASSOCIATION OF TUMOR-NECROSIS-FACTOR-ALPHA AND ITS RECEPTORS WITH THYMIDINE PHOSPHORYLASE EXPRESSION IN INVASIVE BREAST-CARCINOMA

Angiogenesis is an essential requirement for tumour growth and metasta sis and is regulated by a complex network of factors produced by both stromal cells and neoplastic cells within solid tumours. The cytokine tumour necrosis factor alpha (TNF-alpha) and the enzyme thymidine phos phorylase (TP) are two factors known to promote tumour angiogenesis, W e have demonstrated recently that high numbers of tumour-associated ma crophages (TAMs) are significantly associated with increased tumour an giogenesis and poor prognosis in invasive carcinoma of the breast, We have also shown that TAMs are a major source of TNF-alpha in invasive breast carcinomas, and that macrophagelike stromal cells as well as tu mour cells synthesize TP in such tumours, However, little is known of the factors that regulate the production or activity of these factors in the tumour microenvironment, As TNF-alpha has been shown to up-regu late TP expression in tumour cells in vitro we performed an immunohist ochemical study to investigate the possibility that TNF-alpha may be i nvolved in the regulation of TP expression by malignant breast epithel ial cells in vivo. To do this, we used a cocktail of non-neutralizing monoclonal anti-TNF-alpha antibodies to visualize both TNF-alpha-expre ssing macrophages and TNF-alpha bound to its receptors on tumour cells and endothelial cells in a series of 93 invasive carcinomas of the br east, A semiquantitative grading system was then used to compare these staining patterns with that for TP in the same biopsies, TNF-alpha im munoreactivity was also compared with various important tumour variabl es known to relate to outcome in this disease (microvessel density, no de status, grade, stage, receptor status and macrophage infiltration), as well as relapse-free and overall survival data for these patients, Our data show significant positive correlations between TNF-alpha bou nd to its receptors on tumour cells and: (I)TP protein production by t umour cells, and (2) axillary lymph node status (i.e. metastasis). The se results suggest that tumour cell responsiveness to TNF-alpha produc ed by neighbouring TAMs may play a part in the regulation of TP expres sion by tumour cells as well as their metastatic behaviour. This may e xplain, in part, the relationship between increased macrophage infiltr ation and angiogenesis in breast cancer, and further supports the cont ention that TAMs may represent an important target for future anti-ang iogenic therapies.