TGF-beta(1) is elevated in breast cancer tissue and regulates nitric oxideproduction from a number of cellular sources during hypoxia re-oxygenationinjury

Cellular response to treatment is dependent on the metabolic preconditionin g of individual cells, which is a reflection of environmental conditions. W ithin solid tumours there are areas of different oxygen tension, which, we hypothesise, may indicate that cells are exposed to conditions that change continually. Other characteristics of the solid-tumour microenvironment inc lude the production of growth factors, one of which is transforming growth factor (TGF)-beta (1). As part of this study, we measured TGF-beta (1) and found it raised in the serum of breast cancer patients compared with contro ls (98.24 +/- 13.25 vs. 48.87 +/- 12.14 ng/mL; P < 0.05; n = 7), and in the conditioned medium of breast tumour explant tissue compared with matched n ormal tissue (21.1 +/- 5.3 vs. 4.7 +/- 1.2 ng TGF-beta (1)/gram of tissue; P < 0.05; n = 11). Nitric oxide (NO) is a cytotoxic molecule produced by a large number of cells and thought to have antimetastatic properties. In ord er to observe the effect of conditions within breast tumours on NO producti on, we exposed macrophages, endothelial cells and tumour cells to hypoxia r e-oxygenation in vitro, both in the presence and absence of TGF-beta (1). H ypoxia stimulated increased NO production in both macrophages (normoxia: 0. 34 +/- 0.04 nmol/L nitrite vs. hypoxia: 1.04 +/- 0.18 nmol/L nitrite; P < 0 .05) and endothelial cells (normoxia: 0.02 +/- 0.01 nmol/L nitrite vs. hypo xia: 0.21 +/- 0.07 nmol/L nitrite; P < 0.05). NO production in macrophages, endothelial cells and tumour cells was reduced significantly following, hy poxia in the presence of TGF-beta (1) in a concentration-dependent manner. These results suggest that, within breast tumours, tumour-derived TGF-beta (1) in combination with environmental conditions may result in decreased lo cal NO production, which could have implications for tumour growth.