Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

Abstract

Summary Angiogenesis is an essential requirement for tumour growth and metastasis 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-ca) and the enzyme thymidine phosphorylase (TP) are two factors known to promote tumour angiogenesis. We have demonstrated recently that high numbers of tumour-associated macrophages (TAMs) are significantly associated with increased tumour angiogenesis and poor prognosis in invasive carcinoma of the breast. We have also shown that TAMs are a major source of TNF-a in invasive breast carcinomas, and that macrophagelike stromal cells as well as tumour 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-a has been shown to up-regulate TP expression in tumour cells in vitro we performed an immunohistochemical study to investigate the possibility that TNF-a may be involved in the regulation of TP expression by malignant breast epithelial cells in vivo. To do this, we used a cocktail of non-neutralizing monoclonal anti-TNF-a antibodies to visualize both TNF-a-expressing macrophages and TNF-a bound to its receptors on tumour cells and endothelial cells in a series of 93 invasive carcinomas of the breast. A semiquantitative grading system was then used to compare these staining patterns with that for TP in the same biopsies. TNF-a immunoreactivity was also compared with various important tumour variables known to relate to outcome in this disease (microvessel density, node 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-a bound to its receptors on tumour cells and: (1) TP protein production by tumour cells, and (2) axillary lymph node status (i.e. metastasis). These results suggest that tumour cell responsiveness to TNF-a produced by neighbouring TAMs may play a part in the regulation of TP expression by tumour cells as well as their metastatic behaviour. This may explain, in part, the relationship between increased macrophage infiltration and angiogenesis in breast cancer, and further supports the contention that TAMs may represent an important target for future anti-angiogenic therapies.

Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast

“…We have recently demonstrated an association between focal TAM infiltration and reduced relapse-free and overall survival in breast carcinomas. We have also shown that high levels of macrophages in focal areas (MØI) are associated with increased vascular density and that macrophage clusters are found in avascular areas of breast tumours (Leek et al, 1997). As macrophages have been shown to release such proangiogenic cytokines as vascular endothelial growth factor (Harney et al, 1998) tumour recrosis factor α (TNF-α) in response to hypoxia (Scannell et al, 1993), it is possible that, once macrophages reach hypoxic/ischaemic tumour sites, they may promote tumour growth and metastasis by releasing these factors to stimulate angiogenesis.…”

“…As macrophages have been shown to release such proangiogenic cytokines as vascular endothelial growth factor (Harney et al, 1998) tumour recrosis factor α (TNF-α) in response to hypoxia (Scannell et al, 1993), it is possible that, once macrophages reach hypoxic/ischaemic tumour sites, they may promote tumour growth and metastasis by releasing these factors to stimulate angiogenesis. Therefore, the purpose of this study was to assess quantitatively the degree of central necrosis in a consecutive series of invasive breast carcinomas and to examine its relationship to both focal microphage infiltration and angiogenesis, as measured by quantitative CD68 and CD31 immunohistochemistry of vessel and macrophage 'hotspots' respectively (Fox et al, 1995;Leek et al, 1996Leek et al, , 1997.…”

Diagnostic and Prognostic Importance of the Neutrophil Lymphocyte Ratio in Breast Cancer

“…Many cytokines and chemokines are alertable by hypoxia and oxidative stress, which is a most important physiological difference between tumor and normal tissue (Balkwill and Mantovani, 2001) .TNF is a major mediator of inflammation and can be detected in malignant or stromal cells in human cancers especially in breast, ovarian, prostate, bladder and colorectal cancer (Naylor et al, 1993;Burke et al, 1996). In breast cancer infiltrating leucocytes are a major source of TNF (Leek et al, 1998). On the other hand lymphocytic response is the main component in the control of cancer progression.…”

Tumour necrosis factor- α and transforming growth factor- β are significantly associated with better prognosis in non-small cell lung carcinoma: putative relation with BCL-2-mediated neovascularization

“…In a number of immunohistochemical studies TNF-α has appeared in particular in the cytoplasm of inflammatory cells and tumour-associated macrophages (Pusztai et al, 1994), although a proportion of neoplastic cells have shown to be TNF-α positive in some human cancers such as breast (Leek et al, 1998) and lung carcinomas (Tran et al, 1998). Substantially different results have been obtained in these human models: in breast carcinoma a significant association has been found between TNF-α and thymidine phosphorylase expression, which is a factor known to promote tumour angiogenesis (Fajardo et al, 1992;Fox et al, 1996); in lung cancer, where neoangiogenesis seems to play an unfavourable prognostic role, TNF-α expression has shown to produce a better clinical outcome (Tran et al, 1998).…”