Daubriac Julien, Pandya Unnati M, Huang Kuang-Tzu, Pavlides Savvas C, Gama Patricia, Blank Stephanie V, Shukla Pratibha, Crawford Susan E, Gold Leslie I
Department of Medicine, Division of Translational Medicine, New York University School of Medicine Langone Medical Center, New York, New York 10016.
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paolo, Sao Paolo 05508 000, Brazil.
Endocrinology. 2017 Sep 1;158(9):2754-2773. doi: 10.1210/en.2017-00028.
We discovered that pigment epithelium-derived factor (PEDF)-null mice have endometrial hyperplasia, the precursor to human type I endometrial cancer (ECA), which is etiologically linked to unopposed estrogen (E2), suggesting that this potent antiangiogenic factor might contribute to dysregulated growth and the development of type I ECA. Treatment of both ECA cell lines and primary ECA cells with recombinant PEDF dose dependently decreased cellular proliferation via an autocrine mechanism by blocking cells in G1 and G2 phases of the cell cycle. Consistent with the known opposing effects of E2 and progesterone (Pg) on endometrial proliferation, Pg increases PEDF protein synthesis and release, whereas E2 has the converse effect. Using PEDF luciferase promoter constructs containing two Pg and one E2 response elements, E2 reduced and Pg increased promoter activity due to distal response elements. Furthermore, E2 decreases and Pg increases PEDF secretion into conditioned media (CM) by both normal endometrial stromal fibroblasts (ESFs) and cancer-associated fibroblasts (CAFs), but only CM from ESFs mediated growth-inhibitory activity of primary endometrial epithelial cells (EECs). In addition, in cocultures with primary EECs, Pg-induced growth inhibition is mediated by ESFs, but not CAFs. This is consistent with reduced levels of Pg receptors on CAFs surrounding human malignant glands in vivo. Taken together, the data suggest that PEDF is a hormone-regulated negative autocrine mediator of endometrial proliferation, and that paracrine growth inhibition by soluble factors, possibly PEDF, released by ESFs in response to Pg, but not CAFs, exemplifies a tumor microenvironment that contributes to the pathogenesis of ECA.
我们发现，色素上皮衍生因子（PEDF）基因缺失的小鼠患有子宫内膜增生，这是人类I型子宫内膜癌（ECA）的癌前病变，其病因与无对抗性雌激素（E2）有关，这表明这种强大的抗血管生成因子可能导致I型ECA生长失调和发展。用重组PEDF处理ECA细胞系和原发性ECA细胞，通过自分泌机制阻断细胞周期的G1期和G2期，剂量依赖性地降低细胞增殖。与已知的E2和孕酮（Pg）对子宫内膜增殖的相反作用一致，Pg增加PEDF蛋白的合成和释放，而E2则有相反的作用。使用含有两个Pg反应元件和一个E2反应元件的PEDF荧光素酶启动子构建体，由于远端反应元件，E2降低而Pg增加启动子活性。此外，E2降低而Pg增加正常子宫内膜基质成纤维细胞（ESFs）和癌相关成纤维细胞（CAFs）向条件培养基（CM）中分泌PEDF，但只有ESFs来源的CM介导原发性子宫内膜上皮细胞（EECs）的生长抑制活性。此外，在与原发性EECs的共培养中，Pg诱导的生长抑制由ESFs介导，而不是CAFs。这与体内人类恶性腺体周围CAFs上Pg受体水平降低一致。综上所述，数据表明PEDF是一种激素调节的子宫内膜增殖负性自分泌介质，ESFs而非CAFs响应Pg释放的可溶性因子（可能是PEDF）的旁分泌生长抑制，例证了一种有助于ECA发病机制的肿瘤微环境。
