REVIEW Open Access Targeting The Wnt/β-catenin Pathway
Matsuzaki et al. Molecular and Cellular Therapies 2014, VIEWOpen AccessTargeting the Wnt/β-catenin pathway inendometriosis: a potentially effective approachfor treatment and preventionSachiko Matsuzaki1,2,3*, Revaz Botchorishvili1,2,3, Jean Luc Pouly1 and Michel Canis1,2,3AbstractEndometriosis is a chronic, estrogen-dependent disease associated with infertility and pelvic pain. Endometriosis isdefined by the presence of extra-uterine endometrial tissue. It affects approximately 10% of reproductive-aged women.However, the underlying etiology, pathogenesis and pathophysiology remain to be fully elucidated. Knowledgeof these factors is indispensable for the development of targeted therapies for prevention and treatment ofendometriosis. Several studies, including those from our laboratory, have suggested that aberrant activation ofthe Wnt/β-catenin pathway may be involved in the pathophysiology of endometriosis. This is a review of theliterature focused on the aberrant activation of the Wnt/β-catenin pathway in patients with endometriosis, andon how targeting the Wnt/targeting pathway may be a potentially effective approach for treating and/orpreventing endometriosis.Keywords: Endometriosis, Endometrium, Wnt/β-catenin pathwayBackgroundEndometriosis is a chronic, estrogen-dependent diseaseassociated with infertility and pelvic pain. Endometriosisis defined by the presence of extra-uterine endometrialtissue. It affects approximately 10% of reproductive-agedwomen [1]. However, the underlying etiology, pathogenesisand pathophysiology remain to be fully elucidated. Knowledge of these factors is indispensable for the developmentof targeted therapies for prevention and treatment ofendometriosis.Several studies, including those from our laboratory,have suggested that aberrant activation of the Wnt/β-catenin pathway may be involved in the pathophysiologyof endometriosis [2-9]. The Wnt/β-catenin pathway hascrucial roles in embryonic development, tissue self-renewal,and various diseases [10-13]. In the absence of Wnt ligands(“off” state), β-catenin is degraded by the APC/Axin/GSK3ß complex [10-13] (Figure 1A). Binding of Wnt ligandsto the Frizzled transmembrane receptors and their LRP* Correspondence: sachikoma@aol.com1CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, 1, PlaceLucie et Raymond Aubrac, 63003 Clermont-Ferrand, France2Clermont Université, Université d’Auvergne, ISIT UMR6284,Clermont-Ferrand, FranceFull list of author information is available at the end of the articleco-receptors (“on” state) leads to the inactivation ofGSK-3ß and accumulation of β-catenin in the cytoplasm.Then, the elevated cytosolic β-catenin can translocateto the nucleus, where it interacts with the Tcf/LEF transcription factors, leading to transcriptional activation ofWnt-responsive genes (Figure 1B). Many Wnt-responsivegenes have crucial roles in cell proliferation, migration,and invasion [10-13]. These processes are also common inendometriosis [1].This is a review of the literature focused on the aberrantactivation of the Wnt/β-catenin pathway in patients withendometriosis, and on how targeting the Wnt/targetingpathway may be a potentially effective approach for treating and/or preventing endometriosis.ReviewAberrant activation of the Wnt/β-catenin pathway inendometrium of patients with endometriosisMenstrual endometrium of patients with endometriosisPathogenesis of endometriosis remains unclear. However,the implantation theory is the most widely accepted [1].Endometriosis originates from retrograde menstruation ofendometrial tissue that passes through patent Fallopiantubes into the peritoneal cavity. As retrograde menstruation 2014 Matsuzaki et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver ) applies to the data made available in this article,unless otherwise stated.
Matsuzaki et al. Molecular and Cellular Therapies 2014, age 2 of 0B-catTCF/LEF TargetsNucleusTCF/LEFPKF 115-854BCL9TargetsNucleusCGP049090Figure 1 The Wnt/β-catenin signaling pathway. A) In the absence of Wnt ligands such as Wnt1, Wnt3a, and Wnt8 (“off” state), β-catenin isdegraded by the APC/Axin/GSK-3ß complex. B) Binding of Wnt ligands to the Frizzled transmembrane receptors and their LRP co-receptors(“on” state) leads to the inactivation of GSK-3ß and accumulation of β-catenin in the cytoplasm. Then, the elevated cytosolic β-catenin can translocateto the nucleus, where it interacts with the Tcf/LEF transcription factors, leading to transcriptional activation of Wnt-responsive genes. ManyWnt-responsive genes have crucial roles in cell proliferation, migration, and invasion. Two fungal derivatives (PKF 115–854 and CGP049090),small-molecule antagonists of the Tcf/β-catenin complex, disrupt the critical protein-protein interaction between β-catenin and Tcf asindicated in this figure. Effects of PKF 115–854 and/or CGP049090 on endometriosis are summarized in Table 1. APC: adenomatous polyposiscoli, GSK-3ß: glycogen synthase kinase 3β, LRP: lipoprotein receptor-related protein, TCF/LEF: T-cell factor/lymphocyte enhancer factor, CK1:casein kinase, DVL: disheveled.is a common physiological event, it remains unknown whyendometriosis only occurs in about 10% of women duringtheir reproductive years. One possible explanation is thatthe eutopic endometrial cells of women with endometriosismay be functionally and biochemically different from thoseof women without endometriosis [1].Our previous study showed significantly higher totaland active forms of MMP-9 in the menstrual epithelial andstromal cells of patients with endometriosis compared tothose of patients without endometriosis [4]. MMP-9 is oneof the Tcf/β-catenin target genes t genes). Treatment with PKF115–584, a small-molecule antagonist of the Tcf/β-catenincomplex, decreased the amount of total MMP-9 approximately 75% in epithelial cells and 85% in stromal cells inpatients with endometriosis [4]. Furthermore, treatmentwith PKF 115–584 decreased the amount of active MMP9 to undetectable levels in both epithelial and stromal cellsof patients with endometriosis [4]. MMP-9 activity isknown to be involved in cell invasion [14-17]. In addition,recent studies clearly demonstrated that a latent formof MMP-9 may play an important role in cell migration[18,19]. Our previous study demonstrated that theinhibitory effects of cell migration and invasion ofmenstrual endometrial epithelial and stromal cells ofendometriosis patients by treatment with PKF 115–584were much higher than those of patients without endometriosis [4]. These findings are consistent with those of aprevious study that demonstrated that MMP-9 secretion,as assessed by zymography and enzyme-linked immunosorbent assay (ELISA), was increased in womenwith endometriosis compared to healthy women [20].According to the implantation theory, two processesappear to be critical for the establishment of endometriosis:migration and invasion [1,21]. These findings suggestedthat aberrant activation of the Wnt/β-catenin pathwaymay result in increased migration and invasion of menstrual endometrial cells of patients with endometriosis.Furthermore, a recent study showed that human endometrial basal glandular epithelial cells expressed nuclearSOX9, a Wnt target gene, and contained a rare subpopulation of cells with nuclear β-catenin [22]. These findingssuggested that the Wnt pathway was activated in the basalendometrium. They also showed that the embryonic stemcell-surface marker, SSEA-1, marked the human endometrial basal glandular epithelial cells. Interestingly, cells in
Matsuzaki et al. Molecular and Cellular Therapies 2014, topic endometriosis lesions also expressed SSEA-1 andnuclear SOX9, and SOX9 and SSEA-1 expression patternswere similar to those in the matched eutopic basalis epithelia [22]. These investigators speculated that the ectopiclesions might be basalis in origin following retrogrademenstruation [22]. A growing body of evidence suggeststhat endometriosis may arise from stem cells [23-27].The Wnt signaling pathway plays an essential role instem cell regulation [13]. Although further studies arerequired to examine the role of the Wnt/β-catenin signaling in SOX9– and SSEA-1–expressing endometrialglandular epithelial cells, these findings suggested thatmanipulation of Wnt signaling for stem cell regulationmight be a novel therapeutic strategy for preventionand treatment of endometriosis.Mid-secretory endometrium of infertile patients withendometriosisEndometriosis affects approximately 25%-50% of all womenwith infertility [1]. However, the underlying molecularmechanisms of endometriosis-associated infertility remainto be elucidated. One potential cause may be endometrialmolecular defects during the implantation window [1].Previous findings, including those from our laboratory,suggested that the Wnt/beta-catenin signaling pathwaymight be aberrantly activated in infertile patients duringthe mid-secretory phase [2,6,7]. Our previous studydemonstrated punctate membranous expression of dephosphorylated beta-catenin in endometrial epithelialcells of infertile patients during the mid-secretory phase[2]. Expression of the N-terminally dephosphorylatedform of beta-catenin has been shown to be well correlatedwith Wnt activity [28]. Our previous study showed significantly higher basal cell proliferation of endometrialepithelial and stromal cells of patients with endometriosis compared to patients without endometriosis in themid-secretory phase [4]. In addition, mRNA expressionof Cyclin D1, a Tcf/β-catenin target gene, was significantlyhigher in endometrial epithelial cells of patients withendometriosis compared to patients without endometriosis in the mid-secretory phase [4]. Expression levelsof Cyclin D1 tended to be higher in the secretory phasestromal cells of patients with endometriosis comparedto patients without endometriosis, which is in agreement with with the results of a previous study [29].Cell proliferation and Cyclin D1 mRNA expression inepithelial and stromal cells of patients with endometriosiswere effectively decreased by treatment with PKF 115–584, a small-molecule antagonist of the Tcf/β-catenincomplex.A study showed that increased E2 levels activate Wnt/βcatenin signaling to promote endometrial cell proliferationduring the proliferative phase of menstrual cycle, whereasduring the secretory phase, progesterone levels inhibitPage 3 of 7Wnt/β-catenin signaling, resulting in counterbalancingE2-induced proliferation and enhancing differentiation[30]. In addition, a mouse study demonstrated thatstabilization of beta-catenin in the uterus resulted inendometrial glandular hyperplasia and lack of a decidualresponse [31]. In these mice, estrogen receptor (ER)-alphaexpression was increased in the epithelium [31]. A growingbody of evidence suggests that endometrium of patientswith endometriosis has an altered response to progesteroneand persistence of the proliferative phenotype [7,29,32].Studies have demonstrated impaired decidualization inendometrial stromal cells and elevated endometrialER-alpha expression during the mid-secretory phase inpatients with endometriosis [33]. Furthermore, regulationof cyclin D1, one of the target genes of the Wnt pathwayvia activation of β-catenin, is impaired in endometrialstromal cells of patients with endometriosis [7]. Thesefindings suggest that progesterone resistance might fail toinhibit activation of Wnt/β-catenin signaling, resultingin the persistence of the proliferative phenotype andimpaired decidualization in the endometrium of infertile patients with endometriosis during the window ofimplantation.Aberrant activation of the Wnt/β-catenin pathway inendometriosisCell proliferation, migration and invasion of endometriotic cellsThe Wnt/beta-catenin pathway is involved in cell proliferation, migration, and invasion [34], which are alsoinvolved in the pathophysiology of endometriosis [1].Our previous study showed that PKF 115–584, a smallmolecule antagonist of the Tcf/β-catenin complex, couldsignificantly decrease cell proliferation, migration andinvasion of endometrial and endometriotic epithelialand stromal cells [4]. However, our previous findingssuggested that the Wnt/β-catenin signaling pathwaymight not be essential for cell proliferation of endometriotic cells [4]. The inhibitory effect of treatment withPKF 115–584 on cell proliferation in ovarian endometriotic tissue was significantly lower than that of matchedeutopic endometrium of the same patients [4]. The cellproliferation inhibitory effect of deep infiltrating endometriotic tissue and superficial peritoneal endometriotictissue tended to be lower than that of matched eutopicendometrium of the same patients [4]. Furthermore,we showed that in either non-treated or treated cellswith PKF 115–584, no significant difference in thenumber of migrated epithelial and stromal cells wasobserved between endometriotic tissue and matchedeutopic endometrium of the same patients [4]. Inaddition, we observed that no significant difference inpercent inhibition of cell migration by treatment withPKF 115–584 in either epithelial or stromal cells was notedbetween endometriotic tissue and eutopic endometrium of
Matsuzaki et al. Molecular and Cellular Therapies 2014, e same patients [4]. Activation of the Wnt/β-cateninpathway may not be as involved in the cell proliferationand migration of diseased cells—endometriotic cells—thantheir normal cell counterparts—endometrial cells.In contrast, our previous study demonstrated thatendometriotic epithelial cells and stromal cells were moreinvasive than those of matched eutopic endometrium ofthe same patients [4]. These findings are in agreementwith the results of previous in vitro experiments studiesthat showed that endometriotic cells have invasive andmetastatic phenotypes similar to metastatic carcinomacells [35,36]. The numbers of invasive endometriotic epithelial and stromal cells were effectively decreased bytreatment with PKF 115–584 [4]. Levels of active MMP-2in endometriotic epithelial cells and total and activeMMP-9 in endometriotic stromal cells were significantlydecreased compared to those of matched eutopic endometrium following treatment with PKF 115–584 [4]. BothMMP-9 and MMP-2 are Tcf/β-catenin target genes [4].These findings suggested that inhibition of active MMP2and MMP9 by treatment with PKF 115–584 decreasedthe numbers of invasive endometriotic epithelial cells andstromal cells. Aberrant activation of the Wnt/β-cateninsignaling pathway may be involved in the invasive phenotype of endometriotic cells.Furthermore, a recent study demonstrated that theactivated TNFα–MMP-9-SRC-1 axis protects the ectopicendometrium from proinflammatory cytokinemediatedapoptosis [37]. Endometriotic cells exhibit abnormalapoptotic regulation [38]. Aberrant activation of theWnt/β-catenin signaling pathway might also be involvedin resistance of endometriotic stromal cells to apoptosisthrough the TNFα–MMP-9 axis.Recent studies demonstrated the presence of ectopicendometrium in the rectovaginal septum, in the Douglaspouch, in the rectum of human female fetuses [39,40].They hypothesized that ectopic endometrium might bemisplaced outside the uterine cavity during the organogenesis [39,40]. The Wnt/beta-catenin signaling pathwayis essential for organogenesis [41]. Endometriosis in somepatients may arise from müllerian duct remnants. TheWnt/beta-catenin signaling pathway may possibly be activated by hormonal inputs in the ectopic endometriumafter puberty starts [30,42]. However, it is unlikely that allendometriosis could arise from müllerian duct remnants,because the distribution of pelvic endometriosis differsfrom that of embryonic duct remnants.Fibrosis in endometriosisEndometriosis is histologically characterized by dense fibrous tissue mainly composed of collagen type I [1,43].Excess fibrosis may cause severe clinical symptoms, suchas pelvic pain, severe dysmenorrhea, and deep dyspareuniain patients with endometriosis [44,45], Endometriosis isPage 4 of 7an estrogen-dependent disease. However, hormonalsuppressive therapy is not usually effective for deep infiltrating endometriosis [45]. Complete surgical removal of thedeep endometriotic lesions results in the best long-term results and symptomatic relief [45]. However, in addition tothe dense fibrosis, deep infiltrating endometriosis frequentlyinvades vital pelvic organs [45]. Surgical treatment of deepinfiltrating endometriosis should be performed by laparoscopic surgeons who are highly skilled and competent inperforming bowel, bladder, and ureteral surgery [45].Despite of its clinical importance, only a few studieshave been conducted to evaluate new therapies for fibrosisin endometriosis. The cellular and molecular mechanismsunderlying fibrosis in endometriosis remain to be fullyelucidated.Recent studies have demonstrated the involvement ofactivated Wnt/β-catenin signaling in fibrosis in severalorgans [46-50]. Our previous study showed that Wnt3atreatment in the endometrial stromal cells of patientswithout endometriosis significantly increased cell proliferation and migration, cell-mediated contraction ofcollagen gels, and expression of fibrotic marker genes(alpha-smooth muscle actin, type I collagen, connectivetissue growth factor, and fibronectin) [5]. We showed asignificantly lower cell-mediated collagen gel contractionin stromal cells from patients without endometriosis compared to patients with endometriosis [5]. Cell-mediatedcontraction of collagen gel in stromal cells of patientswithout endometriosis was increased by treatment withWnt3a to a level comparable with that of patients withendometriosis [5]. Treatment with Wnt3a induced clearlyvisible αSMA-positive stress fibers, the hallmark ofactivated myofibroblasts, in endometrial stromal cellsof patients without endometriosis. These findings suggested the involvement of the aberrant activation of theWnt/β-catenin pathway in the molecular and cellularmechanisms underlying fibrogenesis of endometriosis [5].Further studies are required whether overexpression ofWnt3a is one of the underlying mechanisms for the development of fibrosis in endometriosis.Furthermore our previous study demonstrated thatmRNA expression of fibrotic marker genes was significantly decreased by treatment with PKF 115–584and CGP049090, small-molecule antagonists of theTcf/β-catenin complex [5]. Treatment with PKF 115–584and CGP049090 significantly decreased stromal cellmediated contraction of collagen gels in endometriumand endometriosis [5]. Our previous study also showedthat cell proliferation and migration of endometrial andendometriotic stromal cells were significantly decreasedby treatment with PKF 115–584 [4]. Fibroblast migration,proliferation, and collagen contraction are main hallmarksof fibrogenesis [51]. Small-molecule antagonists of theTcf/β-catenin complex may inhibit fibrogenesis in
Matsuzaki et al. Molecular and Cellular Therapies 2014, dometriosis [4,5]. Furthermore, we showed that treatment with CGP049090 prevented the progression of fibrosis in a xenograft model of endometriosis in nude mice [5].More importantly, we observed that treatment withCGP049090 revresed established fibrosis in our mousemodel of e
the Wnt/β-catenin pathway may be involved in the pathophysiology of endometriosis. This is a review of the literature focused on the aberrant activation of the Wnt/β-catenin pathway in patients with endometriosis, and on how targeting the Wnt/targeting pathway may be a potentially effecti
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .
On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.
̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions
Dr. Sunita Bharatwal** Dr. Pawan Garga*** Abstract Customer satisfaction is derived from thè functionalities and values, a product or Service can provide. The current study aims to segregate thè dimensions of ordine Service quality and gather insights on its impact on web shopping. The trends of purchases have
Chính Văn.- Còn đức Thế tôn thì tuệ giác cực kỳ trong sạch 8: hiện hành bất nhị 9, đạt đến vô tướng 10, đứng vào chỗ đứng của các đức Thế tôn 11, thể hiện tính bình đẳng của các Ngài, đến chỗ không còn chướng ngại 12, giáo pháp không thể khuynh đảo, tâm thức không bị cản trở, cái được
COUNTY Archery Season Firearms Season Muzzleloader Season Lands Open Sept. 13 Sept.20 Sept. 27 Oct. 4 Oct. 11 Oct. 18 Oct. 25 Nov. 1 Nov. 8 Nov. 15 Nov. 22 Jan. 3 Jan. 10 Jan. 17 Jan. 24 Nov. 15 (jJr. Hunt) Nov. 29 Dec. 6 Jan. 10 Dec. 20 Dec. 27 ALLEGANY Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open .
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
