Abstract
Human uterine fibroids, benign tumors derived from the smooth muscle layers of the uterus, impose a major health burden to up to 50% of premenopausal women in their daily life. To improve our understanding of this disease, we developed and characterized a patient-derived xenograft model by subcutaneous transplantation of pieces of human uterine fibroid tissue into three different strains of severe combined immunodeficient mice. Engrafted uterine fibroid tissue preserved the classical morphology with interwoven bundles of smooth muscle cells and an abundant deposition of collagenous matrix, similar to uterine fibroids in situ. The grafts expressed both estrogen receptor 1 and progesterone receptor. Additionally, both receptors were up-regulated by estrogen treatment. Growth of the fibroid grafts was dependent on 17β-estradiol and progesterone supplementation at levels similar to women with the disease and was studied for up to 60 days at maximum. Co-treatment with the antiprogestin mifepristone reduced graft growth (four independent donors, p<0.0001 two-sided t-test), as did treatment with the mTOR inhibitor rapamycin (three independent donors, p<0.0001 two-sided t-test). This in vivo animal model preserves the main histological and functional characteristics of human uterine fibroids, is amenable to intervention by pharmacological treatment, and can thus serve as an adequate model for the development of novel therapies.
Highlights
Human uterine fibroids (UFs; uterine leiomyoma) are benign tumors of the myometrial layers of the uterus
In this study we demonstrate for the first time a careful analysis of a successful in vivo xenograft model where human fibroids are grown subcutaneously in immunodeficient severe combined immunodeficient (SCID) mice
The grafted tissues maintain the typical characteristics of uterine leiomyomas
Summary
Human uterine fibroids (UFs; uterine leiomyoma) are benign tumors of the myometrial layers of the uterus. By transplanting human fibroid tissues or cells into an immunodeficient mouse strain, patientderived UF in vivo models can be generated, preserving the characteristics of the tumors. Ishikawa et al transplanted pieces of UF tissue under the renal capsule of E2 and P4 supplemented mice Under these conditions, tumors showed significant growth, but the number of grafts and their size was very restricted, and the surgery was rather demanding; making the method not suitable for large scale analysis [23]. The grafted tissue maintains characteristics typical of human fibroids in women This model is very well suited for the evaluation of new treatment modalities and we show that otherwise established inhibitors of UF growth such as rapamycin and mifepristone inhibit growth of patient-derived xenografts
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