Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
J Pathol. 2010 Nov;222(3):261-70. doi: 10.1002/path.2761.
Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17β-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for adenomyosis patients.
子宫腺肌病是一种雌激素依赖性疾病，由子宫内膜向下延伸至子宫肌层引起。上皮-间充质转化（EMT）赋予细胞迁移和侵袭的特性，并可被雌激素诱导。我们假设雌激素诱导的 EMT 在子宫腺肌病的发病机制中起关键作用。我们首先研究了 EMT 是否发生在子宫腺肌病病变中，以及它是否与血清 17β-雌二醇（E2）水平相关。我们对子宫腺肌病患者的子宫腺肌病病变和相应的在位子宫内膜样本进行了免疫组织化学染色。将无子宫内膜疾病的女性的子宫内膜作为对照。在子宫腺肌病病变的上皮成分中，与在位子宫内膜相比，波形蛋白表达上调，E-钙黏蛋白表达下调，表明 EMT 发生在子宫腺肌病中。在子宫腺肌病中，血清 E2 水平与在位子宫内膜和子宫腺肌病病变上皮成分中 E-钙黏蛋白的表达呈负相关，表明雌激素诱导的 EMT 参与了子宫内膜细胞。在雌激素受体阳性的 Ishikawa 子宫内膜上皮细胞中，雌激素诱导其形态发生向成纤维细胞样表型的变化，上皮标志物表达向间充质标志物表达的转变，迁移和侵袭能力增加，以及 EMT 调节因子 Slug 的上调。选择性雌激素受体调节剂雷洛昔芬可阻断这些作用。为了确定雌激素诱导的 EMT 在异位子宫内膜植入中的作用，我们将子宫腺肌病患者的在位子宫内膜或子宫腺肌病病变异种移植到卵巢切除的 SCID 小鼠中。子宫内膜的植入依赖于雌激素，并被雷洛昔芬抑制。综上所述，这些数据强调了雌激素诱导的 EMT 在子宫腺肌病发展中的关键作用，并表明雷洛昔芬可能是子宫腺肌病患者的一种潜在治疗药物。
