ABSTRACT
We previously found that the stable overexpression of oestrogen receptor-alpha in the human endothelial cell line ECV304* inhibits its growth in vitro, and that this inhibition is possibly mediated through a down-regulation of the vasoactive agents endothelin-1 and vascular endothelial growth factor. Here we show an in vivo growth-inhibitory effect of oestrogen receptor-alpha overexpression in tumours initiated in nude mice from the same clone of ECV304. In addition, we show that this growth inhibition is accompanied by an alphavbeta3-mediated inhibition of cell migration in vitro, and a down-regulation of the integrin alphavbeta3, vascular endothelial growth factor and vascularization in vivo. The levels of vascular endothelial growth factor and integrin alphavbeta3, through their effect on cell growth and migration, contribute to the process of angiogenesis and to the pathogenesis of atherosclerosis and cancer. The results shown here demonstrate that a higher level of oestrogen receptor-alpha in the cell, through its effect on certain angiogenic factors, may play a role in the control of angiogenesis.
Subject(s)
Neoplasms, Vascular Tissue/metabolism , Receptors, Estrogen/metabolism , Animals , Antibodies/pharmacology , Cell Division/drug effects , Cell Division/genetics , Cell Line, Transformed , Cell Movement/drug effects , Clone Cells , Down-Regulation/drug effects , Down-Regulation/genetics , Endothelial Growth Factors/metabolism , Endothelial Growth Factors/pharmacology , Estradiol/pharmacology , Estrogen Receptor alpha , Female , Gene Expression/genetics , Humans , Imidazoles/pharmacology , Lymphokines/metabolism , Lymphokines/pharmacology , Mice , Mice, Nude , Neoplasm Transplantation , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/pathology , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/physiopathology , Receptors, Estrogen/genetics , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , Transfection , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of certain female cancers. ER-alpha expression in the ER-negative breast cancer cell lines inhibits their proliferation and invasive, metastatic potential in vitro. We stably overexpressed the ER-alpha in the human endometrial cancer cell line Ishikawa and showed that, unlike estradiol, high levels of ER-alpha significantly inhibit the growth of tumors xenografted from the Ishikawa cells. Subsequent to ER-alpha overexpression, in vivo down-regulation of vascular endothelial growth factor was observed in tumor xenografts. In addition, these tumors showed an inhibition of vascularization and of the angiogenic agent, integrin alphavbeta3. Involvement of a switch in the angiogenic pathways during tumorigenesis has been a recent focus of interest. Our results indicate that a high level of ER-alpha may be beneficial in the control of female cancers because of its inhibitory effect on such angiogenic pathways.
