Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer

Angiogenesis is essential for tumor growth and metastasis and an important prognostic factor in breast cancer. VEGF, a key factor for angiogenesis, has been correlated with tumor vessel density in breast cancer. Estrogen, another crucial factor in breast cancer, stimulates VEGF; and an ERE in the VEGF gene has been defined. VEGF is bioactive in the extracellular fluid, where it becomes available to endothelial cells. Whether E(2) affects VEGF levels in the extracellular fluid is not known. We show, using intratumoral microdialysis in vivo, that E(2) treatment increased tumor extracellular levels of VEGF in an estrogen-dependent breast cancer model. Moreover, extracellular levels of VEGF in the tumor showed a strong correlation with total tumor VEGF, contrary to plasma levels of VEGF. Ninety-three percent of measured VEGF in the extracellular fluid in the tumor was tumor-derived, while only 45% of VEGF in circulating plasma originated from the tumor. We conclude that E(2) increases extracellular VEGF and that microdialysis is a sensitive method for measurement of local VEGF production in vivo. Our results have potential application to the assessment of tumor characteristics in vivo in human tumors for individualized cancer therapy.