Establishment of a novel mouse xenograft model of human uterine leiomyoma

Yusuke Suzuki,Masahide Ohmichi,Masaaki Ii,Takashi Saito,Michio Asahi,Yoshito Terai,Yasuhiko Tabata

doi:10.1038/s41598-018-27138-1

Abstract

Uterine leiomyoma is the most common benign tumour in women, and an appropriate animal model for leiomyoma would be useful for exploring new therapeutic strategies. Therefore, we have been challenged to develop a new simple mouse model for human leiomyoma. Leiomyoma tissues were harvested from myomas resected by different surgical procedures with or without gonadotropin-releasing hormone agonist (GnRHa) treatment and were subcutaneously implanted into BALB/c nude mice with an estradiol/progesterone-releasing pellet. The implanted leiomyoma tissues that were obtained from the marginal site of large myomas resected by abdominal myomectomy with GnRHa treatment exhibited sufficient tumour growth in the transplanted mice. The leiomyomas that were treated with GnRHa highly expressed the estrogen/progesterone receptor genes, insulin-like growth factor 2 (IGF2) and embryonic smooth muscle myosin heavy chain (SMemb), which suggests that these factors are critical in the establishment of a mouse model of growing leiomyoma. As a result, this model will be useful for the development of new therapeutic strategies.

Highlights

Uterine leiomyomas are the most common gynaecologic tumours in women and are a major reason for hysterectomy in Western countries[1,2]
As expected, increased vascularity was observed in both the transplanted uterine muscle layer and leiomyoma, but unexpectedly, the size of the transplanted tissues was reduced both in the uterine muscle layer and in the leiomyoma when MatrigelTM was added. (Fig. 1C–E) On the contrary, both the size of the transplanted uterine muscle layer and that of the leiomyoma were maintained at their original size with reduced vascularity without MatrigelTM compared with those with MatrigelTM. (Fig. 1C–E) We further examined vascularity in the leiomyoma tissue histologically
The serum levels of estradiol and progesterone gradually increased to approximately 800 pg/mL and 8000 pg/mL, respectively, at 6 weeks following implantation of the E2-PLGA and PG-PLGA pellets; these levels peaked at 4 weeks after pellet implantation. (Fig. 2E) The weight gain was evaluated in the mice with transplanted leiomyoma tissues with or without the E2/PG-PLGA pellet at 8 weeks following pellet/tissue implantation, and it was observed that E2/PG supplementation successfully led to an increase in weight. (Fig. 2F) the leiomyoma tissue sections (Masson’s trichrome staining) from the original and the transplanted tissue (4 and 8 weeks after transplantation) exhibited similar histological findings, the fibroblasts stained in blue were distributed evenly at 4 weeks and mainly localized in central site at 8 weeks after making xenograft

Summary

Introduction

Uterine leiomyomas ( called fibroids or myomas) are the most common gynaecologic tumours in women and are a major reason for hysterectomy in Western countries[1,2]. Medical treatment using hormone-based agents (e.g., oral contraceptives, levonorgestrel-containing intrauterine systems (IUSs) and gonadotropin-releasing hormone (GnRH) agonists are available. While these therapies provide varying degrees of control for abnormal uterine bleeding, most of them do not act directly on the leiomyomas, and no definitive agents for the long-term medical treatment of uterine leiomyoma have been developed. Most of the recently developed mouse xenograft models for human leiomyoma require severe immunodeficient mice and growth factor-containing gels with a piece of human leiomyoma tissue[10] or certain cell lines with genetic modifications[11,12,13]. We focused on the size, pretreatment with or without GnRHa, and the portions (central/ marginal) of the leiomyoma that were excised

Methods

Results

Conclusion