Stewart R J, Panigrahy D, Flynn E, Folkman J
Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
J Urol. 2001 Feb;165(2):688-93. doi: 10.1097/00005392-200102000-00095.
The hormonally regulated growth of some human carcinomas represents an important therapeutic target. We report that androgens modulate the angiogenic activity of hormone responsive human prostate cancer.
To define further the critical mechanisms underlying hormone responsiveness we examined the angiogenic mediator, vascular endothelial growth factor messenger (m) RNA and protein in response to androgens in vitro as well as the angiogenic response of xenografts of human prostate cancer after androgen withdrawal in vivo.
In vitro androgen deprivation of LnCaP prostate cancer cells led to decreased vascular endothelial growth factor mRNA and protein expression as well as a 5-fold destabilization in vascular endothelial growth factor mRNA transcripts. In addition, androgen withdrawal inhibited the hypoxic induction of vascular endothelial growth factor mRNA. In mice bearing LnCaP tumors castration resulted in a rapid decrease in mRNA expression and markedly reduced tumor neovascularization.
These findings implicate sex steroids as an important stimulus for vascular endothelial growth factor regulation in hormone sensitive tumors and demonstrate the reversal of neovascularization after hormone withdrawal as an early event in the tumor response to therapy.
某些人类癌症的激素调节生长是一个重要的治疗靶点。我们报告雄激素可调节激素反应性人类前列腺癌的血管生成活性。
为进一步确定激素反应性的关键机制，我们在体外研究了血管生成介质、血管内皮生长因子信使核糖核酸（mRNA）和蛋白对雄激素的反应，以及体内雄激素撤除后人前列腺癌异种移植物的血管生成反应。
体外对LnCaP前列腺癌细胞进行雄激素剥夺导致血管内皮生长因子mRNA和蛋白表达降低，以及血管内皮生长因子mRNA转录本稳定性下降5倍。此外，雄激素撤除抑制了血管内皮生长因子mRNA的低氧诱导。在携带LnCaP肿瘤的小鼠中，去势导致mRNA表达迅速下降，并显著减少肿瘤新生血管形成。
这些发现表明性类固醇是激素敏感肿瘤中血管内皮生长因子调节的重要刺激因素，并证明激素撤除后新生血管形成的逆转是肿瘤对治疗反应的早期事件。
