title: TGF-beta1 is elevated in breast cancer tissue and regulates nitric oxide production from a number of cellular sources during hypoxia re-oxygenation injury.
abstract: Cellular response to treatment is dependent on the metabolic preconditioning of individual cells, which is a reflection of environmental conditions. Within 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 include the production of growth factors, one of which is transforming growth factor (TGF)-beta1. As part of this study, we measured TGF-beta1 and found it raised in the serum of breast cancer patients compared with controls (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 normal tissue (21.1+/-5.3 vs. 4.7+/-1.2 ng TGF-beta1/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 order to observe the effect of conditions within breast tumours on NO production, we exposed macrophages, endothelial cells and tumour cells to hypoxia re-oxygenation in vitro, both in the presence and absence of TGF-beta1. Hypoxia 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. hypoxia: 0.21+/-0.07 nmol/L nitrite; P < 0.05). NO production in macrophages, endothelial cells and tumour cells was reduced significantly following hypoxia in the presence of TGF-beta1 in a concentration-dependent manner. These results suggest that, within breast tumours, tumour-derived TGF-beta1 in combination with environmental conditions may result in decreased local NO production, which could have implications for tumour growth.
authors.affiliation: Department of Surgery, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin. surgres@iol.ie
authors.forename: D
authors.initials: D
authors.lastname: Toomey
authors.forename: C
authors.initials: C
authors.lastname: Condron
authors.forename: Q D
authors.initials: QD
authors.lastname: Wu
authors.forename: E
authors.initials: E
authors.lastname: Kay
authors.forename: J
authors.initials: J
authors.lastname: Harmey
authors.forename: P
authors.initials: P
authors.lastname: Broe
authors.forename: C
authors.initials: C
authors.lastname: Kelly
authors.forename: D
authors.initials: D
authors.lastname: Bouchier-Hayes
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
chemical_list: D016212:Transforming Growth Factor beta; D009569:Nitric Oxide