Development and Validation of Hormonal Impact of a Mouse Xenograft Model for Human Uterine Leiomyoma.

ABSTRACT

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 mm3 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.