The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten.
The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten.
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Pten 的子宫上皮损失不足以诱导具有完整基质 Pten 的子宫内膜癌。
DOI：
10.1371/journal.pgen.1007630
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发表时间：
2018-08
期刊：
影响因子：
4.5
通讯作者：
Dey SK
中科院分区：
文献类型：
--
作者：
Liang X;Daikoku T;Terakawa J;Ogawa Y;Joshi AR;Ellenson LH;Sun X;Dey SK
肿瘤抑制因子Pten的突变通常导致包括子宫在内的各种器官的肿瘤发生。我们先前表明，使用Pgr-Cre驱动程序（Ptenf/fPgrCre/+）在小鼠子宫中缺失Pten会导致子宫内膜癌（EMC）的快速发展并完全渗透。我们还报道了使用Amhr 2-Cre在基质和子宫肌层中的Pten缺失未能启动EMC。由于Ptenf/fPgrCre/+子宫上皮主要受肿瘤发生的影响，尽管其在上皮和基质中均丢失，我们想知道单独在上皮中的Pten缺失是否会诱导肿瘤发生。我们发现，在Ltf-iCre驱动下子宫上皮Pten缺失的小鼠（Ptenf/f/LtfCre/+）发生子宫复合体非典型增生（CAH），但即使在6个月大时也很少发生EMC。我们观察到Ptenf/fPgrCre/+子宫表现出独特的细胞角蛋白5（CK 5）和转化相关蛋白63（p63）阳性上皮细胞群;这些细胞标志着复层上皮和鳞状分化。相比之下，Ptenf/fLtfCre/+增生性上皮不经历分层，但经历广泛的上皮细胞凋亡。这种增加的细胞凋亡与子宫基质中TGFβ水平的升高和下游效应物SMAD 2/3的激活有关。我们的研究结果表明，间质PTEN通过TGFβ信号抑制上皮细胞从增生转化为癌。总之，这项研究，使用组织特异性的Pten缺失，突出了上皮间质的串扰在子宫内膜癌的发生。子宫内膜癌在美国是非常普遍的妇科癌症。Pten是起源于上皮的子宫内膜癌中最常见的突变基因。以前的研究集中在PTEN在上皮生长调节中的作用。在这里，我们表明，除了在上皮细胞中的Pten突变，其在间质室的突变是子宫内膜癌的发生和发展的关键。我们目前的证据表明，虽然在子宫上皮和间质中的Pten功能的损失导致子宫内膜癌的快速发展，其在上皮细胞中的损失导致子宫内膜增生，但不是癌。我们的研究结果强调了间质PTEN在增生向癌转化中的关键作用，而间质TGFβ似乎在阻止这种转化中起作用。这项研究揭示了一个以前未确定的作用，PTEN在影响子宫微环境的起始和产生子宫内膜癌。
Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Ptenf/fPgrCre/+) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Ptenf/fPgrCre/+ uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver (Ptenf/f/LtfCre/+) develop uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Ptenf/fPgrCre/+ uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Ptenf/fLtfCre/+ hyperplastic epithelia do not undergo stratification, but extensive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten, highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma. Endometrial cancer is highly prevalent gynecological cancer in the United States. Pten is the most commonly mutated gene in endometrial carcinoma originating in the epithelium. Previous studies focused on PTEN’s role in epithelial growth regulation. Here we show that in addition to Pten mutation in the epithelium, its mutation in the stromal compartment is critical for the initiation and progression of endometrial carcinoma. We present evidence that while loss of Pten function in both uterine epithelia and stroma results in rapid development of endometrial carcinoma, its loss in epithelial cells leads to endometrial hyperplasia, but not carcinoma. Our findings highlight the critical role of stromal PTEN in the transformation of hyperplasia to carcinoma and stromal TGFβ appears to play a role in preventing this transformation. This study reveals a previously unidentified role of PTEN in influencing the microenvironment in the uterus for the initiation and generation of endometrial carcinoma.
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