MAMMARY FIBROBLASTS MAY INFLUENCE BREAST-TUMOR ANGIOGENESIS VIA HYPOXIA-INDUCED VASCULAR ENDOTHELIAL GROWTH-FACTOR UP-REGULATION AND PROTEIN EXPRESSION

Recent studies demonstrate the relationship of microvessel density to malignant progression in breast cancer (N. Weidner, J. P. Semple, W. R . Welch, and J. Folkman, N. Engl. J. Med., 324: 1-8, 1991), underscori ng the importance of angiogenesis in this tumor, Crucial in tumor angi ogenesis are the paracrine actions of tumor-secreted factors (e.g., va scular endothelial growth factor), which have been thought to derive f rom the tumor epithelial cells themselves. We demonstrate that in resp onse to hypoxic conditions, human mammary fibroblasts dramatically up- regulate vascular endothelial growth factor mRNA and increase vascular endothelial growth factor protein levels in accordance with the degre e of oxygen deprivation. Thus, mammary stromal cells, only recently co nsidered in the regulation of breast carcinomas, may play a hitherto u nrealized role in breast cancer angiogenesis.