Neovascularization is essential for the growth of solid tumors, including breast cancer. Vascular endothelial growth factor (VEGF) represents a major angiogenic molecule in human breast cancer and is expressed in both invasive and in situ carcinomas. Our main emphasis is on the biological significance of VEGF and its tyrosine kinase receptors, flt-1 and KDR, in breast cancer development. With the use of a one-vector Tet system, we demonstrated that VEGF was essential for the early establishment of tumors, derived from subcutaneously transplanted breast carcinoma cells. In this model, administration of tetracycline in the drinking water throughout the experimental period resulted in 60% inhibition of endogenous VEGF and no tumor development. This suggests that VEGF, in addition to its angiogenic activity, plays a critical role at the prevascular stage of tumor establishment. Studies are ongoing to find out if the function of VEGF as a vascular permeability factor is important at the prevascular stage. The growth inhibitory effect of the tetracycline-mediated VEGF suppression decreased as the tumors became larger and when the tumors reached 10 mm, other angiogenic factors, including bFGF and TGF alpha emerged and could fully compensate for the lack of the VEGF activity. These findings may have important implications for the present pursuit of VEGF as a target for anti- angiogenic therapy of cancer. Continued studies on the mechanism of action of the tumor vascular targeting agent flavone acetic acid (FAA), showed stimulation of endothelial nitric oxide synthase activity and formation of the toxic peroxynitrite radical within subcutaneous mouse tumors. Production of nitric oxide and peroxynitrite correlated with the appearance of apoptotic tumor cells. Further, we found that FAA treatment impairs mitochondrial function and stimulates apoptosis of cultured endothelial cells. These effects were reversed by inhibitors of superoxide and nitric oxide production.
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