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Micrographs of case 46 with 10 tumor nodules, considered a mitotically active leiomyoma during the preliminary examination (A and B), proven to be a leiomyosarcoma by re-sampling (C and D) following the X-chromosomal inactivation assay (see Fig. 9). (A) More cellular tumor area composed of spindle cells, with its leiomyogenic phenotypes demonstrated by positive immunoreactivities for smooth muscle actin and desmin (data not shown). (B) Tumor area showing massive hyalinization, with an osteoid appearance. (C) Tumor area with coagulative necrosis. (D) Highly cellular area with more mitotic figures (arrowheads). Magnification: A and C, x240; B, x120; D, x480. Stained with hematoxylin and eosin.
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Uterine leiomyomas were shown to be clonal lesions, but the relationship among different tumor nodules in multiple uterine leiomyomas remains unresolved. In this study, X-chromosomal inactivation patterns of these tumor nodules were shown by allelic polymorphism analysis through polymerase-chain reaction at the phosphoglycerate kinase and androgen...
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The cellular origin of tumors induced by the chemical carcinogen 3-methylcholanthrene (MCA) was studied in mice with X-chromosome inactivation mosaicism. Because only one of the two X-chromosomes is active in XX somatic cells, a female heterozygous at the X-linked phosphoglycerate kinase (PGK-1) locus for the usual Pgk-1b gene and the variant Pgk-1...
Citations
... Data on genetic aberrations also serve as an auxiliary tool in the clonal origin analysis of ULs and other tumours. Whereas the majority of multiple myomas in the uterus emerge independently from one another, in some cases, different myomas could be clonally linked and could share the same chromosomal abnormalities [139,[213][214][215][216]. Molecular studies have shown that such ULs can additionally acquire individual genetic mutations conformed with the branched tumour evolution model [217]. ...
Uterine leiomyomas (ULs), frequent benign tumours of the female reproductive tract, are associated with a range of symptoms and significant morbidity. Despite extensive research, there is no consensus on essential points of UL initiation and development. The main reason for this is a pronounced inter- and intratumoral heterogeneity resulting from diverse and complicated mechanisms underlying UL pathobiology. In this review, we comprehensively analyse risk and protective factors for UL development, UL cellular composition, hormonal and paracrine signalling, epigenetic regulation and genetic abnormalities. We conclude the need to carefully update the concept of UL genesis in light of the current data. Staying within the framework of the existing hypotheses, we introduce a possible timeline for UL development and the associated key events—from potential prerequisites to the beginning of UL formation and the onset of driver and passenger changes.
... Mashal et al studied the pattern of X-chromosome-linked inactivation of phosphoglycerokinase in fibroid cells, concluding that the monoclonal pattern of a single inactive allele likely suggested a unicellular origin (100). Fibroids have also been shown to exhibit an intrinsic growth rate independent of other fibroids within the same uterus (101). ...
Selective progesterone receptor modulators (SPRMs) are new class of compounds developed to target the progesterone receptor with a mix of agonist and antagonist properties. These compounds have been introduced for treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, progesterone receptor modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US FDA in 2012 for treatment of Cushing syndrome due to its additional anti-glucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.
... Genetic abnormalities affecting specific TICs might play pivotal roles in the tumourigenesis of uterine leiomyoma (Ono et al., 2012) (Fig. 2). Therefore, considering that uterine leiomyomas are monoclonal tumors (Linder and Gartler, 1965;Hashimoto et al., 1995;Wang et al., 2002;Canevari et al., 2005;Zhang et al., 2006;Cai et al., 2007), it is possible that the dysregulation of MyoSCs or committed cells that acquire stem-like features (TICs) could be responsible for this benign condition (Gargett, 2007;Teixeira et al., 2008;Holdsworth-Carson et al., 2014;Mas et al., 2014). This hypothesis suggests that TICs are organized hierarchically, similarly to normal tissues, although they would arise from the transformation of SSCs after the acquisition of tissue-specific genetic changes (Jordan et al., 2006). ...
Background:
Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells.
Objective and rationale:
In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others.
Search methods:
A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus.
Outcomes:
The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation.
Wider implications:
More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
... The same mutation was not present in the leiomyoma tissue of the patient; and therefore, we can assume that a) the mutation has occurred in the lung BML lesion only; b) the patient suffered from multiple leiomyomas, and the pulmonary BML did not arise from that particular uterine leiomyoma tissue analysed in the current study; or c) BML does not originate from leiomyoma. It has been demonstrated that leiomyomas develop as clonal lesions but multiple nodules in a single uterus may have different clonal origin [31] and harbour different chromosomal aberrations [32]. Also, the study by Wu et al. revealed shared somatic mutations only in two out of three pairs of uterine leiomyoma and BML metastases [8]. ...
Background:
Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML.
Case presentation:
We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X-chromosome inactivation assay.
Conclusions:
We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X-chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases.
... There is a general agreement in the literature that myomas are of monoclonal origin. The clonality of ULs was studied using X-linked glucose-6-phosphate dehydrogenase (G6PD) isoenzymes, for the discrimination between active and inactive alleles of the X-linked genes [46][47][48][49]. Even if the monoclonality of ULs seems sufficiently studied, there are reports of some biclonal or oligoclonal cancers [50]. ...
Purpose:
Despite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas.
Methods:
Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases.
Results:
Several studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14-q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-β3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion.
Conclusion:
The new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future.
... Human uterine fibroids are clonal in origin, as confirmed by studying the inactivation of heterozygous-status alleles on the X chromosome [11]. Additionally, recent studies have confirmed that the different cell types contained in fibroids (mainly smooth muscle cells and fibroblasts) are all clonally derived from a parental cell with implied multipotent stem cell properties [12]. ...
... Moreover, the introduction of let-7 microRNA in cultures of cells from these large myomas (with relative HMGA2 overexpression) resulted in a reduction of HMGA2 protein. However, it is hard to imagine that in vivo regulation of HMGA2 by let-7 has a specific functional role in fibroids or is the only factor contributing to tumor genesis and growth [11,31]. ...
... In contrast to the surrounding myometrial tissue, UFs are hypoxic, but fail to show typical responses to hypoxia such as upregulation of HIF1alpha [9]. In patients with multiple UFs, both unicentric and multicentric development of the tumors has been demonstrated [10]. ...
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.
... Human uterine leiomyomas are clonal in origin, which has been confirmed by analysis of the inactivation status of heterozygous alleles on the X chromosome (Linder and Gartler, 1965; Townsend et al., 1970; Nilbert and Strö mbeck, 1992; Mashal et al., 1994; Hashimoto et al., 1995; Baschinsky et al., 2000; Wang et al., 2002; Canevari et al., 2005; Zhang et al., 2006; Cai et al., 2007). This technique exploits the fact Genetic clues in fibroid biology that in each cell one of the X chromosomes is randomly inactivated during gastrulation. ...
BACKGROUND Uterine leiomyomas (fibroids) are highly prevalent benign smooth muscle tumors of the uterus. In the USA, the lifetime risk
for women developing uterine leiomyomas is estimated as up to 75%. Except for hysterectomy, most therapies or treatments often
provide only partial or temporary relief and are not successful in every patient. There is a clear racial disparity in the
disease; African-American women are estimated to be three times more likely to develop uterine leiomyomas and generally develop
more severe symptoms. There is also familial clustering between first-degree relatives and twins, and multiple inherited syndromes
in which fibroid development occurs. Leiomyomas have been described as clonal and hormonally regulated, but despite the healthcare
burden imposed by the disease, the etiology of uterine leiomyomas remains largely unknown. The mechanisms involved in their
growth are also essentially unknown, which has contributed to the slow progress in development of effective treatment options.
... Several genetic studies based on the unique isoenzyme pattern (7,8), X-inactivation (9,10), and DNA methylation-sensitive HUMARA assay (11) have demonstrated that uterine fibroids are monoclonal in origin. Accordingly, some studies have proposed that these benign tumors could originate from a single dysregulated myometrial smooth muscle stem cell, under the influence of ovarian hormones (6,12,13). ...
... Accumulated evidence indicates a clonal origin of uterine fibroids, probably from a deranged myometrial stem cell (7)(8)(9)(10)(11). Stro-1 þ /CD44 þ MyoF and Stro-1 þ /CD44 þ F cells and primary cells (PrMyoF/PrF) were seeded in triplicate at 156 cells/cm 2 under hypoxic conditions (2% O 2 , 37 C, 5% CO 2 , 90% humidity) to determine CE. ...
To identify and characterize myometrial/fibroid stem cells by specific stem cell markers in human myometrium, and to better understand the stem cell contribution in the development of uterine fibroids.
Prospective, experimental human and animal study.
University research laboratory.
Women undergoing hysterectomy for treatment of symptomatic uterine fibroids and female NOD/SCID/IL-2Rγ(null) mice.
Identification and isolation of stem cells from human fibroids and adjacent myometrium tissues using Stro-1/CD44-specific surface markers.
Flow cytometry, semiquantitative polymerase chain reaction, clonogenicity assays, cell culture, molecular analysis, immunocyto-histochemistry, in vitro differentiation, and xenotransplantation assays.
Using Stro-1/CD44 surface markers, we were able to isolate stem cells from adjacent myometrium and human fibroid tissues. The undifferentiated status of isolated cells was confirmed by the expression of ABCG2 transporter, as well as additional stem cell markers OCT4, NANOG, and GDB3, and the low expression of steroid receptors ERα and PR-A/PR-B. Mesodermal cell origin was established by the presence of typical mesenchymal markers (CD90, CD105, and CD73) and absence of hematopoietic stem cell markers (CD34, CD45), and confirmed by the ability of these cells to differentiate in vitro into adipocytes, osteocytes, and chondrocytes. Finally, their functional capability to form fibroid-like lesions was established in a xenotransplantation mouse model. The injected cells labeled with superparamagnetic iron oxide were tracked by both magnetic resonance imaging and fluorescence imaging, thus demonstrating the regenerative potential of putative fibroid stem cells in vivo.
We have demonstrated that Stro-1/CD44 can be used as specific surface markers to enrich a subpopulation of myometrial/fibroids cells, exhibiting key features of stem/progenitor cells. These findings offer a useful tool to better understand the initiation of uterine fibroids, and may lead to the establishment of effective therapeutic options.
Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
... Although fibroids are of benign nature, they often cause symptoms such as infertility, recurrent miscarriage and extensive bleeding. First demonstrated based on their unique isoenzyme pattern (Townsend et al., 1970) and X-inactivation studies (Canevari et al., 2005;Cai et al., 2007;Mashal et al., 1994), a clonal origin of fibroids was reported recently by a more sensitive and reliable method conducted by Holdsworth-Carson et al. (2013). Hence, it could be considered that fibroids arise from a single mutated cell likely having stem/ progenitor cell characteristics. ...
Uterine fibroids are the most common gynecological tumors affecting women in their reproductive age. Despite this high incidence
the pathogenesis of fibroids is widely unsolved. Whereas formerly only imbalances in hormonal levels were considered to account
for tumor development, the identification of genetic changes likely to affect myometrial stem cell reservoirs provided a novel
approach to fibroid genesis. Here, we identified a certain subset of cells by the surface marker CD24 with increased abundance
in fibroids compared with myometrial tissue. Fibroid cells expressing CD24 shared certain features of immature or progenitor-like
cells such as quiescence, reduced expression of smooth muscle differentiation markers and elevated expression of genes involved
in the wingless-type (WNT)-pathway such as beta-catenin. In addition, a positive correlation between CD24 and wingless-type family member 4 (WNT4) expression was observed in uterine fibroids with mediator subcomplex 12 gene (MED12) mutations. Our findings suggest that cells highly expressing CD24 represent a type of immature smooth muscle progenitor
cells. Their accumulation might be driven by disturbed differentiation processes caused by genetic changes possibly involving
MED12 mutations or high mobility group AT-hook (HMGA)2 rearrangements.
