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.