Memy I: a novel murine model for uterine leiomyoma using adenovirus-enhanced human fibroid explants in severe combined immune deficiency mice

Abstract

OBJECTIVE-This study was undertaken to develop a representative murine model for human leiomyoma.STUDY DESIGN-Human fibroid tumor tissues were cut into small pieces and treated with medium alone, adenoviral-β-galactosidase, adenoviral-vascular endothelial growth factor-A, adenoviral-cyclooxygenase-2, or both adenoviral-vascular endothelial growth factor-A and adenoviral-cyclooxygenase-2. Tissue pieces were inserted subcutaneously in the flank of each severe combined immunodeficient mouse. The developed lesion was measured twice per week. Xenograft tissues were harvested after 30 days and analyzed.RESULTS-Tissue pieces transfected with both adenoviral-cyclooxygenase-2 and adenoviralvascular endothelial growth factor-A continued to grow up to 30 days postimplantation. The number of proliferating and apoptotic cells, as well as the expression of smooth muscle actin, desmin, vimentin, estrogen receptors, and progesterone receptors was similar between retrieved grafts from that group and the original patient tissue. Furthermore, hematoxylin and eosin and Masson's Trichrome stains confirmed this similarity.CONCLUSION-Human uterine leiomyoma xenografts, pretreated with both adenoviralcyclooxygenase-2 and adenoviral-vascular endothelial growth factor-A and implanted subcutaneously in severe combined immunodeficient mice, represent a novel model for human uterine leiomyoma. Uterine leiomyomas, commonly referred to as fibroids, are benign tumors that arise in the myometrial compartment of the uterus. 1 Leiomyomas are well-differentiated smooth muscle tumors with a relatively low mitotic index 1 ; tumors can become quite large and are usually multiple. Uterine leiomyomas are the most common gynecologic neoplasm, occurring in more than 70% of reproductive-age women. 1 When symptomatic, leiomyomas are associated with infertility, menorrhagia, and spontaneous abortion. They are the leading indication for hysterectomy in premenopausal women. 1 The high frequency of these tumors and lack of satisfactory nonsurgical and fertility-preserving treatments make uterine leiomyomas a significant reproductive health concern for women. 1 The underlying causes of uterine leiomyomas are poorly understood, as a result, in part, of the absence of a good model system with which to study these tumors. The only available animal model is the Eker rat in which both leiomyosarcomas and leiomyomas are observed. 2 Female Eker rats have uterine leiomyomas develop by 12 to 16 months of age with a frequency of about 65%. 2 The predisposing genetic alteration in these animals is an insertion of an endogenous retrovirus between exons 30 and 31 of the Tsc-2 gene, which inactivates the encoded tumor suppressor protein. This leads to the development of tumors in several different organs, such as the spleen, kidneys, lungs, and uterus. 2 Although the Eker rat has been valuable as an animal model for uterine leiomyoma, there are limitations regarding difficulty in breeding, low penetrance, high cost, and sarcoma-like histology that hinder its use as a...

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…Using immunohistochemical studies, Gentry and colleagues found that vascular endothelial growth factor-A (VEGF-A) was overexpressed significantly in leiomyoma tissue as compared to the adjacent myometrium (103). It was demonstrated that VEGF is necessary for the growth of leiomyoma xenografts in vivo (104). VEGF represents a potential therapeutic target in leiomyoma, and Xu and colleagues demonstrated that it is downregulated by the selective progesterone receptor modulator CDB-2914 (105).…”

Oestrogen-Induced Angiogenesis and Implantation Contribute to the Development of Parasitic Myomas after Laparoscopic Morcellation

“…Nonetheless, the Tsc2-driven tumour development might not reflect the sporadic pathogenesis of myomas. An alternative model described by Hassan et al [41], who provoked growth of myoma-like xenograft implanted subcutaneously in SCID mice, by transplanting human tumour tissue pieces overexpressing COX2 (cyclooxygenase 2) and VEGF through adenoviral transduction. However, that model exhibits substantial limitations because it is driven by the ectopic overexpression of COX2 [42][43][44].…”

“…Of note, Ishikawa et al showed that the growth of tissue xenografts was strongly dependent on the cell density of the xenografts [22]. Hassan et al showed VEGF provoked growth of myoma-like xenografts implanted subcutaneously in SCID mice [41]. VEGFenhanced angiogenesis is also associated with an increase in vascular permeability, which results in an increase in the amount of growth factors and nutrients delivered to tumour cells [44,50].…”

Establishment of a Novel Xenograft Model for Human Uterine Leiomyoma in Immunodeficient Mice

“…Serum estrogen levels were maintained at high levels by subcutaneous implantation of 1.5 mg, 60-day sustained-release 17β -estradiol pellets (Innovative Research of America, Sarasota, FL, USA) as described previously (Hassan et al 2008). The pellets were implanted 2 days before the tissue transplantation.…”

“…Recently, to overcome such limitations, Memy I, a novel human uterine leiomyoma xenograft model, was developed. Human uterine xenografts pretreated with both adenoviral-cyclooxygenase-2 (COX-2) and adenoviral-vascular endothelial growth factor-A (VEGF-A) were implanted subcutaneously into severe combined immunodeficient (SCID) mice (Hassan et al 2008). In this model, human leiomyoma tissue could be engrafted and survive for at least 1 month.…”