title: Application of a Patient Derived Xenograft Model for Predicative Study of Uterine Fibroid Disease.
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.
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fritsch
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmidt
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Gröticke
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Frisk
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Keator
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Koch
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, United States of America.
authors.forename: Ov D
authors.initials: OD
authors.lastname: Slayden
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D064593:Heterografts; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D015735:Mifepristone / Q000008:administration & dosage*; D011980:Receptors, Progesterone / Q000096:biosynthesis
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D011980:Receptors, Progesterone; D015735:Mifepristone