Department of Pathology, Hospices Civils de Lyon, Centre de Biologie et de Pathologie Sud, Chemin du Grand Revoyet, Université de Lyon, Université Claude Bernard Lyon I, 69495, Pierre Bénite Cedex, France.
INSERM 1052, CNRS 5286 Cancer Research Center of Lyon, Equipe labellisée Ligue contre le Cancer, Université de Lyon, Université Claude Bernard Lyon I, 28 rue Laennec, 69373, Lyon Cedex 08, France.
Virchows Arch. 2019 Jul;475(1):85-94. doi: 10.1007/s00428-019-02532-w. Epub 2019 Feb 9.
Several subtypes of high-grade endometrial carcinomas (ECs) contain an undifferentiated component of non-epithelial morphology, including undifferentiated and dedifferentiated carcinomas and carcinosarcomas (CSs). The mechanism by which an EC undergoes dedifferentiation has been the subject of much debate. The epithelial-mesenchymal transition (EMT) is one of the mechanisms implicated in the transdifferentiation of high-grade carcinomas. To improve our understanding of the role of EMT in these tumors, we studied a series of 89 carcinomas including 14 undifferentiated/dedifferentiated endometrial carcinomas (UECs/DECs), 49 CSs (21 endometrial, 29 tubo-ovarian and peritoneal), 17 endometrioid carcinomas (grade 1-3), and 9 high-grade serous carcinomas of the uterus, using a panel of antibodies targeting known epithelial markers (Pan-Keratin AE1/AE3 and E-cadherin), mesenchymal markers (N-cadherin), EMT transcription factors (TFs) (ZEB1, ZEB2, TWIST1), PAX8, estrogen receptors (ER), progesterone receptors (PR), and the p53 protein. At least one of the three EMT markers (more frequently ZEB1) was positive in the sarcomatous component of 98% (n = 48/49) of CSs and 98% (n = 13/14) of the undifferentiated component of UEC/DEC. In addition, 86% of sarcomatous areas of CSs and 79% of the undifferentiated component of UEC/DEC expressed all three EMT-TFs. The expression of these markers was associated with the loss of or reduction in epithelial markers (Pan-keratin, E-cadherin), PAX8, and hormone receptors. In contrast, none of the endometrioid and serous endometrial carcinomas expressed ZEB1, while 6% and 36% of endometrioid and 11% and 25% of serous carcinomas focally expressed ZEB2 and TWIST1, respectively. Although morphologically different, EMT appears to be implicated in the dedifferentiation in both CSs and UEC/DEC. Indeed, we speculate that the occurrence of EMT in a well differentiated endometrioid carcinoma may consecutively lead to a dedifferentiated and undifferentiated carcinoma, while in a type II carcinoma, it may result in a CS.
几种高级别子宫内膜癌（EC）亚型含有非上皮形态的未分化成分，包括未分化和去分化癌和癌肉瘤（CS）。EC 经历去分化的机制一直是争论的主题。上皮-间充质转化（EMT）是涉及高级别癌的转化的机制之一。为了提高我们对 EMT 在这些肿瘤中的作用的理解，我们研究了一系列 89 例癌，包括 14 例未分化/去分化子宫内膜癌（UEC/DEC）、49 例 CS（21 例子宫内膜、29 例卵巢和腹膜）、17 例子宫内膜样癌（1 级-3 级）和 9 例子宫高级别浆液性癌，使用一组针对已知上皮标志物（Pan-Keratin AE1/AE3 和 E-cadherin）、间充质标志物（N-cadherin）、EMT 转录因子（TF）（ZEB1、ZEB2、TWIST1）、PAX8、雌激素受体（ER）、孕激素受体（PR）和 p53 蛋白的抗体。在 98%（n=48/49）的 CS 和 98%（n=13/14）的 UEC/DEC 的未分化成分的肉瘤成分中，至少有一个 EMT 标志物（更常见的是 ZEB1）呈阳性。此外，86%的 CS 的肉瘤区域和 79%的 UEC/DEC 的未分化成分表达了所有三个 EMT-TFs。这些标志物的表达与上皮标志物（Pan-keratin、E-cadherin）、PAX8 和激素受体的缺失或减少有关。相比之下，没有子宫内膜样和浆液性子宫内膜癌表达 ZEB1，而 6%和 36%的子宫内膜样癌和 11%和 25%的浆液性癌分别局灶性表达 ZEB2 和 TWIST1。尽管形态上不同，但 EMT 似乎与 CS 和 UEC/DEC 的去分化有关。事实上，我们推测 EMT 在分化良好的子宫内膜样癌中的发生可能会导致去分化和未分化癌，而在 II 型癌中，它可能导致 CS。
