Uterine leiomyoma (UL) is the most common gynaecologic tumour, affecting an estimated 70 to 80% of women. Leiomyomas develop from the transformation of myometrial stem cells into leiomyoma stem (or ...tumour‐initiating) cells. These cells undergo self‐renewal and differentiation to mature cells, both are necessary for the maintenance of tumour stem cell niche and tumour growth, respectively. Wnt/β‐catenin and TGF‐β/SMAD pathways, both overactive in UL, promote stem cell self‐renewal, crosstalk between stem and mature cells, cellular proliferation, extracellular matrix (ECM) accumulation and drive overall UL growth. Recent evidence suggests that simvastatin, an antihyperlipidemic drug, may have anti‐leiomyoma properties. Herein, we investigated the effects of simvastatin on UL stem cells. We isolated leiomyoma stem cells by flow cytometry using DyeCycle Violet staining and Stro‐1/CD44 surface markers. We found that simvastatin inhibits proliferation and induces apoptosis in UL stem cells. In addition, it also suppressed the expression of the stemness markers Nanog, Oct4 and Sox2. Simvastatin significantly decreased the production of the key ECM proteins, collagen 1 and fibronectin. Finally, it inhibited genes and/or proteins expression of TGF‐β1, 2 and 3, SMAD2, SMAD4, Wnt4, β‐Catenin, LRP6, AXIN2 and Cyclin D1 in UL stem cells, all are key drivers of the TGF‐β3/SMAD2 and Wnt4/β‐Catenin pathways. Thus, we have identified a novel stem cell‐targeting anti‐leiomyoma simvastatin effect. Further studies are needed to replicate these findings in vivo.
Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no ...effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.
Role of vitamin D in uterine fibroid biology Brakta, Soumia, M.D; Diamond, Justin S., B.S; Al-Hendy, Ayman, M.D., Ph.D ...
Fertility and sterility,
09/2015, Letnik:
104, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Objective To provide a detailed summary of current scientific knowledge on uterine fibroids (leiomyomas) in vitro and in in vivo animal models, as well as to postulate the potential role of vitamin ...D3 as an effective, inexpensive, safe, long-term treatment option for uterine fibroids. Design PubMed search articles were used to identify the most relevant studies on uterine fibroids, as well as effects of vitamin D3 on uterine fibroid cells and fibroid tumor growth in in vivo animal models. Setting University research laboratory. Patient(s) Not applicable. Intervention(s) None. Main Outcome Measure(s) Not applicable. Result(s) Despite numerous publications available on uterine fibroids, information about the role that vitamin D3 plays in the regulation of uterine fibroids is limited. Most of the recent vitamin D3–related studies on uterine fibroids were published from our group. Recent studies have demonstrated that vitamin D deficiency plays a significant role in the development of uterine fibroids. Our recent studies have demonstrated that vitamin D3 reduces leiomyoma cell proliferation in vitro and leiomyoma tumor growth in in vivo animal models. These results postulate the potential role of vitamin D3 for an effective, safe, nonsurgical medical treatment option for uterine fibroids. Conclusion(s) This article reviews human and animal studies and uncovers new possibilities for understanding the vitamin D–based therapeutic option for an effective, safe, long-term treatment of uterine fibroids. On the basis of these results, a clinical trial with vitamin D3 or a hypocalcemic analog, paricalcitol, may be warranted for nonsurgical medical treatment of uterine fibroids.
Despite the high prevalence and major negative impact of uterine fibroids (UFs) on women's health, their pathogenesis remains largely unknown. While tumor‐initiating cells have been previously ...isolated from UFs, the cell of origin for these tumors in normal myometrium has not been identified. We isolated cells with Stro1/CD44 surface markers from normal myometrium expressing stem cell markers Oct‐4/c‐kit/nanog that exhibited the properties of myometrial stem/progenitor‐like cells (MSCs). Using a murine model for UFs, we showed that the cervix was a hypoxic “niche” and primary site (96%) for fibroid development in these animals. The pool size of these MSCs also responded to environmental cues, contracting with age and expanding in response to developmental environmental exposures that promote fibroid development. Translating these findings to women, the number of MSCs in unaffected human myometrium correlated with risk for developing UFs. Caucasian (CC) women with fibroids had increased numbers of MSCs relative to CC women without fibroids, and African‐American (AA) women at highest risk for these tumors had the highest number of MSCs: AA‐with fibroids > CC‐with fibroids > AA‐without fibroids > CC‐without fibroids. These data identify Stro1+/CD44+ MSCs as MSC/progenitor cell for UFs, and a target for ethnic and environmental factors that increase UF risk. Stem Cells 2017;35:666–678
Early life exposure to environmental toxicants during the sensitive period of uterine development, expands the number of myometrial stem cells as well as permanently reprograms and attenuates key DNA damage repair gene capacity, leading to the development of uterine fibroids. This paradigm shifting concept provides translational implications of value to evaluate if real time quantification of the number of stem cells in a tissue, such as myometrium, could be a predictor of future tumor risk. Importantly, it presents a foundation for an individualized approach for stem cell based targeted therapy of tumors.
In two international, randomized, double-blind, 24-week, phase 3 trials involving women with uterine fibroid–associated heavy menstrual bleeding, therapy with relugolix (an oral ...gonadotropin-releasing hormone receptor antagonist), combined with estradiol and norethindrone acetate, led to a significant reduction in menstrual bleeding while preserving bone mineral density.
Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. Although benign, UFs are associated with ...significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. A knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve UF patient outcomes. Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. This review summarizes the recent progress of ascertaining the biological functions and regulatory mechanisms in UFs, from the perspective of factors regulating ECM production, ECM-mediated signaling, and pharmacological drugs targeting ECM accumulation. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of the extracellular matrix in the pathogenesis of UFs and in applications. Comprehensive and deeper insights into ECM-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with this common tumor.
In two identical, double-blind, randomized, 6-month phase 3 trials, elagolix (an oral gonadotropin-releasing hormone antagonist), administered with hormonal add-back therapy (estradiol, 1 mg, and ...norethindrone acetate, 0.5 mg, once daily) was more effective in reducing heavy menstrual bleeding in women with uterine fibroids than placebo. Bone loss was attenuated with add-back therapy, as compared with elagolix alone.
Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis and high rates of recurrence and metastasis. The origin and molecular mechanism underlying ...and driving its clinical and biological behavior remain largely unknown. Recently, we and others have revealed the role of microRNAs, DNA methylation, and histone modifications in contributing to the pathogenesis of uLMS. However, the connection between reversible m6A RNA methylation and uLMS pathogenesis remains unclear. In this study, we assessed the role and mechanism of FTO m6A RNA demethylase in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that the levels of RNA demethylases FTO and ALKBH5 were aberrantly upregulated in uLMS tissues compared to adjacent myometrium with a significant change by histochemical scoring assessment (p < 0.01). Furthermore, the inhibition of FTO demethylase with its small, potent inhibitor (Dac51) significantly decreased the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-seq analysis revealed that the inhibition of FTO with Dac51 exhibited a significant decrease in cell-cycle-related genes, including several CDK members, and a significant increase in the expression of CDKN1A, which correlated with a Dac51-exerted inhibitory effect on cell proliferation. Moreover, Dac51 treatment allowed the rewiring of several critical pathways, including TNFα signaling, KRAS signaling, inflammation response, G2M checkpoint, and C-Myc signaling, among others, leading to the suppression of the uLMS phenotype. Moreover, transcription factor (TF) analyses suggested that epitranscriptional alterations by Dac51 may alter the cell cycle-related gene expression via TF-driven pathways and epigenetic networks in uLMS cells. This intersection of RNA methylation and other epigenetic controls and pathways provides a framework to better understand uterine diseases, particularly uLMS pathogenesis with a dysregulation of RNA methylation machinery. Therefore, targeting the vulnerable epitranscriptome may provide an additional regulatory layer for a promising and novel strategy for treating patients with this aggressive uterine cancer.
Objective To evaluate the effects and mechanisms of action of vitamin D on human uterine leiomyoma (HuLM) cell proliferation in vitro. Design Laboratory study. Setting University hospitals. ...Patients(s) Not applicable. Interventions(s) Not applicable. Main Outcome Measure(s) HuLM cells were treated with 1,25-dihydroxyvitamin D3 (vitamin D), and cell proliferation was assayed by the methylthiazolyl tetrazolium technique. proliferating cell nuclear antigen (PCNA), BCL-2, BCL-w, cyclin-dependent kinase (CDK) 1, and catechol- O -methyltransferase ( COMT ) protein levels were analyzed by Western blotting. COMT mRNA and enzyme activity were assayed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and high-performance liquid chromatography analysis, respectively. The role of COMT was evaluated in stable HuLM cells by silencing COMT expression. Result(s) Vitamin D inhibited the growth of HuLM cells by 47 ± 0.03% at 1 μM and by 38 ± 0.02% at 0.1 μM compared with control cells at 120 hours of treatment. Vitamin D inhibited extracellular signal–regulated kinase activation and down-regulated the expression of BCL-2, BCL-w, CDK1, and PCNA. Western blot, RT-PCR, and enzyme assay of COMT demonstrated inhibitory effects of vitamin D on COMT expression and enzyme activity. Silencing endogenous COMT expression abolished vitamin D–mediated inhibition of HuLM cell proliferation. Conclusion(s) Vitamin D inhibits growth of HuLM cells through the down-regulation of PCNA, CDK1, and BCL-2 and suppresses COMT expression and activity in HuLM cells. Thus, hypovitaminosis D appears to be a risk factor for uterine fibroids.
Objective
To investigate the effects of 52 weeks of treatment with relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) on symptoms of uterine fibroids (UF) ...and quality of life (QoL) in women with heavy menstrual bleeding associated with UF and anemia (hemoglobin ≤10.5 g/dL) at baseline.
Methods
This post hoc analysis included women from the LIBERTY long‐term extension study with anemia (hemoglobin concentration ≤10.5 g/dL) at pivotal study baseline and documented hemoglobin values at week 52 (anemia‐evaluable population). Treatment responders: women achieving a menstrual blood loss volume of <80 mL and a ≥50% reduction over the last 35 days of treatment. Anemia responders were women achieving a hemoglobin increase of >2 g/dL from baseline to week 52. Least squares (LS) mean changes from baseline in uterine fibroid symptom (UFS)‐QoL symptom severity, fatigue, and health‐related QoL total (HR‐QoL) and (sub)scale scores were calculated.
Results
In total, 115 women were included in the anemia‐evaluable population. Of 39 anemia‐evaluable women who received continuous treatment with relugolix combination therapy for 52 weeks, 34 (87.2%) met treatment responder criteria and 23 (59.0%) were anemia responders. LS mean hemoglobin concentration increased by 29.4% at week 52. LS mean UFS‐QoL symptom severity and fatigue scores decreased by 38.5 and 31.9 points, respectively, and HR‐QoL total score increased by 41.6 points.
Conclusion
In women with UF and a high disease burden due to anemia, relugolix combination therapy substantially improved hemoglobin levels, decreased distress due to symptoms, especially fatigue, over 52 weeks.
Synopsis
Relugolix combination therapy improved hemoglobin, reduced fatigue and other symptoms, and improved quality of life in women with uterine fibroids and anemia.
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