Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, Maryland 21201-1559, USA.
Endocrinology. 2011 Dec;152(12):4481-8. doi: 10.1210/en.2011-1449. Epub 2011 Sep 27.
After decades of research, the mechanism by which estrogens stimulate the proliferation of epithelial cells in the endometrium and mammary gland, and in the carcinomas that arise in those tissues, is still not understood. Cells do not proliferate in response to 17β-estradiol (E2) alone, and although it is widely recognized that growth factors play a role in E2's proliferative effect, exactly how they are involved is unclear. It has long been known that the proliferation of endometrial epithelial cells is preceded by dramatic increases in blood flow and microvascular permeability, filling the subepithelial stroma with plasma and the proteins it contains, such as IGF-I, which is known to synergize with E2 in the induction of cell proliferation. The hyperpermeability is caused by vascular endothelial growth factor (VEGF), which is rapidly induced by E2, via the transcription factors hypoxia-inducible factor 1 and estrogen receptor α, in luminal epithelial cells in vivo. As we recently showed, VEGF is also strongly induced in endometrial cancer cells in vitro when excessive degradation of hypoxia-inducible factor 1α, caused by the abnormally high oxygen level to which cultured cells are exposed, is prevented. Putting these facts together, we now propose a new model of E2-induced proliferation in which VEGF-induced vascular hyperpermeability plays an essential role. E2 first induces the expression by endometrial epithelial cells of VEGF, which then acts in a paracrine manner to induce interendothelial cell gaps in subepithelial blood vessels, through which plasma and the proteins therein enter the adjacent stroma. Plasma carries even more E2, which circulates bound to proteins, and IGF-l, which together drive epithelial cells completely through the cell cycle.
经过几十年的研究，雌激素刺激子宫内膜和乳腺上皮细胞以及这些组织中发生的癌增殖的机制仍未被理解。细胞不会单独对 17β-雌二醇（E2）增殖作出反应，尽管广泛认为生长因子在 E2 的增殖作用中起作用，但它们如何参与其中尚不清楚。长期以来，人们一直知道子宫内膜上皮细胞的增殖是在血流量和微血管通透性急剧增加之前发生的，使上皮下基质充满血浆及其所含的蛋白质，如 IGF-I，已知它与 E2 协同作用诱导细胞增殖。这种高通透性是由血管内皮生长因子（VEGF）引起的，E2 通过转录因子缺氧诱导因子 1 和雌激素受体 α 体内在腔上皮细胞中迅速诱导 VEGF 的产生。正如我们最近所表明的，当培养细胞暴露的异常高氧水平阻止缺氧诱导因子 1α 的过度降解时，体外子宫内膜癌细胞中也会强烈诱导 VEGF。将这些事实放在一起，我们现在提出了一个新的 E2 诱导增殖模型，其中 VEGF 诱导的血管通透性增加起着至关重要的作用。E2 首先诱导子宫内膜上皮细胞表达 VEGF，然后 VEGF 通过旁分泌方式在子上皮血管中的内皮细胞之间诱导间隙，通过这些间隙，血浆及其内含物进入相邻基质。血浆携带更多的 E2，它与蛋白质结合循环，IGF-l 共同驱动上皮细胞完全通过细胞周期。
