体外受精生成的人类胚胎微环境通过诱导癌症干细胞分化来逆转子宫内膜癌细胞中的孕激素抵抗。
The IVF-generated human embryonic microenvironment reverses progestin resistance in endometrial cancer cells by inducing cancer stem cell differentiation.
机构信息
Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China; Reproductive Medicine Center, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
出版信息
Cancer Lett. 2022 Feb 1;526:311-321. doi: 10.1016/j.canlet.2021.11.003. Epub 2021 Nov 12.
Progestin resistance is a critical factor that prevents patients with endometrial cancer (EC) from receiving conservative therapy. However, the etiology remains elusive. Cancer stem cells (CSCs) may be a contributing factor to progestin resistance in EC. These cells share similar stemness properties with embryonic stem cells that have a multipotent but differential naïve phenotype. Embryonic stem cells are programed to self-renew, to differentiate and to show plasticity toward a normal cellular phenotype in their defined microenvironment. However, whether this microenvironment may promote CSC differentiation toward a better responsive phenotype and reverse progestin resistance has not yet been clarified. In the current study, we found that progestin resistance of endometrial CSCs can be improved or reversed by using in vitro fertilization (IVF)-generated embryonic sac-derived fluid containing the embryonic microenvironment. Furthermore, suppression or reversal of progestin resistance was mediated by placental alkaline phosphatase (ALPP), a factor secreted into the embryonic microenvironment by IVF-generated blastocysts. ALPP significantly reversed progestin resistance by facilitating endometrial CSC differentiation through downregulating the stemness genes NANOG, OCT4 and SOX2. We further showed that the downregulation of NANOG, OCT4 and SOX2 by ALPP was carried out by TET1/2-mediated epigenetic modulation of the promoter regions of these genes. Such changes at the molecular level initiated endometrial CSC differentiation and promoted a better responsive endometrial cancer phenotype. In fact, their response to progestin treatment was similar to that of well-differentiated endometrioid carcinoma cells without CSCs. ALPP could be a novel target in the process to overcome progestin resistance, and such findings may provide a new approach for the conservative treatment of endometrial cancer.
孕激素抵抗是阻止子宫内膜癌（EC）患者接受保守治疗的关键因素。然而，其病因仍不清楚。癌症干细胞（CSC）可能是 EC 孕激素抵抗的一个促成因素。这些细胞与胚胎干细胞具有相似的干性特征，具有多能性但分化为原始表型。胚胎干细胞被编程为自我更新、分化，并在其定义的微环境中表现出向正常细胞表型的可塑性。然而，这种微环境是否可以促进 CSC 向更好反应性表型分化并逆转孕激素抵抗尚未阐明。在本研究中，我们发现使用含有胚胎微环境的体外受精（IVF）生成的胚胎囊衍生液可以改善或逆转子宫内膜 CSC 的孕激素抵抗。此外，孕激素抵抗的抑制或逆转是由胎盘碱性磷酸酶（ALPP）介导的，ALPP 是由 IVF 生成的胚泡分泌到胚胎微环境中的一种因子。ALPP 通过下调干性基因 NANOG、OCT4 和 SOX2 显著逆转孕激素抵抗，从而促进子宫内膜 CSC 分化。我们进一步表明，ALPP 通过 TET1/2 介导的这些基因启动子区域的表观遗传修饰来下调 NANOG、OCT4 和 SOX2。这些分子水平的变化启动了子宫内膜 CSC 的分化，并促进了更好反应性的子宫内膜癌表型。事实上，它们对孕激素治疗的反应与没有 CSC 的分化良好的子宫内膜样腺癌细胞相似。ALPP 可能是克服孕激素抵抗过程中的一个新靶点，这些发现可能为子宫内膜癌的保守治疗提供新方法。
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