Brandt Laura P, Albers Joachim, Hejhal Tomas, Catalano Antonella, Wild Peter J, Frew Ian J
Institute of Physiology, University of Zurich, Zurich, Switzerland.
Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
PLoS One. 2017 Oct 5;12(10):e0186102. doi: 10.1371/journal.pone.0186102. eCollection 2017.
The uterine corpus represents the most common site for tumour development in the female genital system. Uterine neoplasms are categorised as epithelial, mesenchymal, mixed epithelial-mesenchymal or trophoblastic tumours. In this study we employed a mouse genetic approach using the MuLE lentiviral gene regulatory system to functionally test the ability of ecotropic lentiviruses to model epithelial and mesenchymal uterine malignancies ex vivo and in vivo. We discovered that MuLE lentiviruses efficiently infect uterine stromal cells but not endometrial epithelial cells when injected into the uterus of cycling, pseudopregnant or ovarectomized mice. Consistent with this cellular infection spectrum, we show that intra-uterine injection of ecotropic MuLE viruses expressing oncogenic HrasG12V together with knockdown of Cdkn2a induce high-grade endometrial stromal sarcomas. These findings establish this approach as an efficient method of generating autochthonous mouse models of uterine sarcomas and in general for performing genetic manipulations of uterine stromal cells in vivo.
子宫体是女性生殖系统中肿瘤发生最常见的部位。子宫肿瘤可分为上皮性、间质性、上皮 - 间质性混合性或滋养层肿瘤。在本研究中，我们采用小鼠遗传学方法，利用MuLE慢病毒基因调控系统，在体外和体内功能测试亲嗜性慢病毒模拟上皮性和间质性子宫恶性肿瘤的能力。我们发现，当将MuLE慢病毒注入处于发情周期、假孕或卵巢切除的小鼠子宫时，其能有效感染子宫基质细胞，但不能感染子宫内膜上皮细胞。与这种细胞感染谱一致，我们表明，子宫内注射表达致癌性HrasG12V的亲嗜性MuLE病毒并敲低Cdkn2a可诱导高级别子宫内膜间质肉瘤。这些发现确立了该方法作为生成子宫肉瘤自体小鼠模型以及总体上在体内对子宫基质细胞进行基因操作的有效方法。
