Dataset Information

Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting.

ABSTRACT: Uterine leiomyoma (UL) or fibroid is a benign smooth muscle tumor of the myometrium with a lifetime incidence of approximately 70%. ULs often require medical intervention due to severe symptoms such as heavy menstrual bleeding and abdominal pain. Although the most common and effective management of ULs is surgical removal, the invasive surgical procedure imposes physical and psychological burdens on the patients. Moreover, the economic burden of UL on health care system is enormous due to the high cost of surgeries. Thus, therapeutic options with long-term efficacy to replace surgical management are urgently needed. For the development of such medical options, reliable preclinical research models are imperative. Ex vivo culture of UL cells has been the primary research model for decades. However, recent studies demonstrated that primary cell culture is not a suitable model for UL research, as primary cultures of ULs mostly consist of non-tumor fibroblasts. Here we describe the protocol for patient-derived xenograft of UL, which faithfully replicates the phenotypes of human UL in situ.

SUBMITTER: Serna VA

PROVIDER: S-EPMC6289531 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting.

Serna Vanida Ann VA Kurita Takeshi T

Journal of biological methods 20180416 2

Uterine leiomyoma (UL) or fibroid is a benign smooth muscle tumor of the myometrium with a lifetime incidence of approximately 70%. ULs often require medical intervention due to severe symptoms such as heavy menstrual bleeding and abdominal pain. Although the most common and effective management of ULs is surgical removal, the invasive surgical procedure imposes physical and psychological burdens on the patients. Moreover, the economic burden of UL on health care system is enormous due to the hi ...[more]

PMID: 30547045

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Project description:Study questionDoes halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model?Summary answerHF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis.What is known alreadyUterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas.Study design, size, durationPrimary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group.Participants/materials, setting, methodsMouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF.Main results and the role of chanceTreatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P < 0.05) reduction in tumor volume. The HF-induced volume reduction was accompanied by increased apoptosis and decreased cell proliferation. In contrast, there was no significant change in the collagen content either at the transcript or protein level between UL xenografts in control and HF groups. HF treatment did not change the expression level of ovarian steroid hormone receptors. No adverse pathological effects were observed in other tissues from mice undergoing treatment at these doses.Limitations, reasons for cautionWhile this study did test the effects of HF on human leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear.Wider implications of the findingsThe results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery.Study funding/competing interestsThis project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests.

Project description:BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p<0.001) and prolonged survival (p=0.004) compared to the vehicle control.ConclusionsA metastatic PE-derived RMC PDX model was established and shown to maintain histologic features of the patient cancer. Molecular integrity of the PDX models was well maintained between renal tumor and PE PDX as well as between two successive renal tumor PDX generations. Using the PE PDX model, sunitinib demonstrated therapeutic efficacy for RMC. This model can serve as a foundation for future mechanistic and therapeutic studies for primary and metastatic RMC.

Dataset Information

Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting.

Publications

Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting.

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