Malik Minnie, Britten Joy, Catherino William H
Department of Obstetrics and Gynecology, Building A, Room 3082, Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Reprod Sci. 2020 Jun;27(6):1304-1317. doi: 10.1007/s43032-019-00123-3. Epub 2020 Feb 3.
Multiple in vivo animal models for uterine leiomyoma do not adequately represent human disease based on etiology, molecular phenotype, or limited fixed life span. Our objective was to develop a xenograft model with sustained growth, by transplanting a well-established actively growing three-dimensional (3D) cell culture of human leiomyoma and myometrium in NOD/SCID ovariectomized female mice. We demonstrated continued growth to at least 12 weeks and the overexpression of extracellular matrix (ECM). Further, we confirmed maintenance of hormonal response that is comparable to human disease in situ. Leiomyoma xenografts under hormonal treatment demonstrated 8 to12-fold increase of volume over the xenografts not treated with hormones. Estradiol-treated xenografts were more cellular as compared to progesterone or combination milieu, at the end of 8-week time frame. There was also a non-statistically significant 2-4 mm increase in volume between 8-week and 12-week xenografts with higher matrix to cell ratio in 12-week xenografts compared to the 8-week and placebo xenografts. Increased expression of ECM proteins, fibronectin, versican, and collagens, indicated an actively growing cell matrix formation in the xenografts. In conclusion, we have developed and validated a xenograft in vivo model for uterine leiomyoma that shares the genomic and proteomic characteristics with the human surgical specimens of origin and recapitulates the most important features of the human tumors, the aberrant ECM expression that defines the leiomyoma phenotype and gonadal hormone regulation. Using this model, we demonstrated that combination of estradiol and progesterone resulted in increased cellularity and ECM production leading to growth of the xenograft tumors.
基于病因、分子表型或有限的固定寿命，多种子宫平滑肌瘤的体内动物模型并不能充分代表人类疾病。我们的目标是通过将已建立的、活跃生长的人平滑肌瘤和子宫肌层的三维（3D）细胞培养物移植到NOD/SCID卵巢切除的雌性小鼠中，开发一种具有持续生长能力的异种移植模型。我们证明了其持续生长至少12周，并出现细胞外基质（ECM）的过表达。此外，我们证实了其激素反应的维持情况与人类原位疾病相当。接受激素治疗的平滑肌瘤异种移植瘤的体积比未接受激素治疗的异种移植瘤增加了8至12倍。在8周时间框架结束时，与孕酮或联合环境相比，经雌二醇处理的异种移植瘤细胞更多。在8周和12周的异种移植瘤之间，体积也有2至4毫米的非统计学显著增加，12周的异种移植瘤与8周和安慰剂异种移植瘤相比，基质与细胞的比例更高。ECM蛋白、纤连蛋白、多功能蛋白聚糖和胶原蛋白的表达增加，表明异种移植瘤中正在形成活跃生长的细胞基质。总之，我们已经开发并验证了一种子宫平滑肌瘤的体内异种移植模型，该模型与人类起源的手术标本具有相同的基因组和蛋白质组特征，并概括了人类肿瘤的最重要特征，即定义平滑肌瘤表型的异常ECM表达和性腺激素调节。使用该模型，我们证明雌二醇和孕酮的联合使用导致细胞增多和ECM产生增加，从而导致异种移植瘤的生长。
