@article{5420262c2bb44e638de4734e0fcd7f11,
title = "The IVF-generated human embryonic microenvironment reverses progestin resistance in endometrial cancer cells by inducing cancer stem cell differentiation",
abstract = "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 na{\"i}ve 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.",
keywords = "CSC, Differentiation, Embryonic microenvironment, Endometrial cancer, Progestin resistance",
author = "Di Sun and Zuoshu Qin and Yuan Xu and Qimeng Xiao and Yiqing Xu and Mingzhu Bai and Wen Li and Yong Liu and Wenxin Zheng and Zhenbo Zhang",
note = "Funding Information: The authors thank Prof. Zhao Shimin (Fudan University, Shanghai, China) for providing the plasmids pcDNA3.0-TET1-flag and pRSF-Duet1-IDH1. We also thank Prof. Shi Yujiang (Harvard University, Cambridge, MA) for providing pPB-TET1 plasmid. This work was supported by grants from the National Key Technology R&D Program of China (2019YFC1005200 and 2019YFC1005201), National Natural Science Foundation of China (grants 81872111 and 81672562), Shanghai Municipal Science and Technology Committee of Shanghai outstanding academic leaders plan (19XD1423100), the project of Outstanding Medical Doctor for ZZ, Shanghai Municipal Education Commission?Gaofeng Clinical Medicine Grant Support (20181713, 20181714), Shanghai Talent Development Foundation (2019121), Shanghai Municipal Science and Technology Committee of Multi-center Clinical Study Project (20Z21900400), Shanghai Collaborative Innovation Center of Translational Medicine (TM202015), Shanghai Songjiang Leading Talent Program. Funding Information: The authors thank Prof. Zhao Shimin (Fudan University, Shanghai, China) for providing the plasmids pcDNA3.0-TET1-flag and pRSF-Duet1-IDH1. We also thank Prof. Shi Yujiang (Harvard University, Cambridge, MA) for providing pPB-TET1 plasmid. This work was supported by grants from the National Key Technology R&D Program of China ( 2019YFC1005200 and 2019YFC1005201 ), National Natural Science Foundation of China (grants 81872111 and 81672562 ), Shanghai Municipal Science and Technology Committee of Shanghai outstanding academic leaders plan ( 19XD1423100 ), the project of Outstanding Medical Doctor for ZZ, Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support ( 20181713 , 20181714 ), Shanghai Talent Development Foundation ( 2019121 ), Shanghai Municipal Science and Technology Committee of Multi-center Clinical Study Project ( 20Z21900400 ), Shanghai Collaborative Innovation Center of Translational Medicine ( TM202015 ), Shanghai Songjiang Leading Talent Program. Publisher Copyright: {\textcopyright} 2021",
year = "2022",
month = feb,
day = "1",
doi = "10.1016/j.canlet.2021.11.003",
language = "English (US)",
volume = "526",
pages = "311--321",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
}