RESUMO
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.
Assuntos
Neoplasias de Tecido Vascular/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Anticorpos/farmacologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Linhagem Celular Transformada , Movimento Celular/efeitos dos fármacos , Células Clonais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fatores de Crescimento Endotelial/metabolismo , Fatores de Crescimento Endotelial/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio , Feminino , Expressão Gênica/genética , Humanos , Imidazóis/farmacologia , Linfocinas/metabolismo , Linfocinas/farmacologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias de Tecido Vascular/genética , Neoplasias de Tecido Vascular/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Receptores de Estrogênio/genética , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , Transfecção , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
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.
