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Chapela PJ, Broaddus RR, Hawkins SM, Lessey BA, Carson DD. Cytokine stimulation of MUC4 expression in human female reproductive tissue carcinoma cell lines and endometrial cancer. J Cell Biochem 2016; 116:2649-57. [PMID: 25923310 DOI: 10.1002/jcb.25213] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 04/22/2015] [Indexed: 12/27/2022]
Abstract
MUC4, a transmembrane glycoprotein, interferes with cell adhesion, and promotes EGFR signaling in cancer. Studies in rat models have demonstrated steroid hormonal regulation of endometrial MUC4 expression. In this study, qRT-PCR screening of mouse tissues determined that Muc4 mRNA also was robustly expressed in mouse uteri. Previous studies from our labs have demonstrated MUC4 mRNA was expressed at levels <1% of MUC1 mRNA in human endometrium and endometriotic tissue. Multiple human endometrial adenocarcinoma cell lines were assayed for MUC4 mRNA expression revealing extremely low basal expression in the Ishikawa, RL-95-2, AN3CA, and KLE lines. Moderate to high expression was observed in HEC50 and HEC-1A cells. MUC4 mRNA expression was not affected by progesterone and/or estrogen treatment, but was greatly stimulated at both mRNA and protein levels by proinflammatory cytokines (IFN-γ and TNF-α), particularly when used in combination. In endometrial tissue, MUC4 mRNA levels did not change significantly between normal or cancerous samples; although, a subset of patients with grade 1 and 2 tumors displayed substantially higher expression. Likewise, immunostaining of human endometrial adenocarcinoma tissues revealed little to no staining in many patients (low MUC4), but strong staining in some patients (high MUC4) independent of cancer grade. In cases where staining was observed, it was heterogeneous with some cells displaying robust MUC4 expression and others displaying little or no staining. Collectively, these observations demonstrate that while MUC4 is highly expressed in the mouse uterus, it is not a major mucin in normal human endometrium. Rather, MUC4 is a potential marker of endometrial adenocarcinoma in a subset of patients.
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Affiliation(s)
| | - Russell R Broaddus
- Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030
| | - Shannon M Hawkins
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, 77030
| | - Bruce A Lessey
- Department of Obstetrics and Gynecology, Greenville Health System, Greenville, South Carolina, 29605
| | - Daniel D Carson
- Department of Biosciences, Rice University, Houston, Texas, 77251.,Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030
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Abstract
The process of embryonic implantation needs coordinated development and communication between the blastocyst and the maternal endometrium. Considerable advances in the understanding of the cell biology of the human embryo and maternal endometrium have been achieved separately. However, the communication between them, and the reciprocal effects on each other, constitute a complicated and yet unsolved question in reproductive medicine that must be further investigated. A paracrine dialogue between the embryo, endometrium and the corpus luteum is known to occur in other species such as rodents and primates. The aim of this work is to present updated information on the embryonic regulation of endometrial epithelial molecules such as adhesion molecules, anti-adhesion molecules, cytoskeletal proteins, chemokines and leptin during the apposition and adhesion phases of human implantation.
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Affiliation(s)
- A Pellicer
- Instituto Valenciano de Infertilidad Foundation (FIVIER), Valencia, Spain.
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Song Y, Wang Q, Huang W, Xiao L, Shen L, Xu W. NF κB expression increases and CFTR and MUC1 expression decreases in the endometrium of infertile patients with hydrosalpinx: a comparative study. Reprod Biol Endocrinol 2012; 10:86. [PMID: 23061681 PMCID: PMC3551815 DOI: 10.1186/1477-7827-10-86] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 10/10/2012] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Hydrosalpinx are associated with infertility, due to reduced rates of implantation and increased abortion rates. The aims of this study were to investigate the expression of cystic fibrosis transmembrane conductance regulator (CFTR), nuclear factor kappa B (NF KappaB) and mucin-1 (MUC-1), and analyze the correlation between the expression of CFTR and NF KappaB or MUC1, in the endometrium of infertile women with and without hydrosalpinx. METHODS Thirty-one infertile women with laparoscopy-confirmed unilateral or bilateral hydrosalpinx and 20 infertile women without hydrosalpinx or pelvic inflammatory disease (control group) were recruited. Endometrial biopsy samples were collected and the expression of CFTR, NF KappaB and MUC1 were analyzed using immunohistochemistry and quantitative real-time PCR. RESULTS CFTR, NF KappaB and MUC1 mRNA and protein expression tended to increase in the secretory phase compared to the proliferative phase in both groups; however, these differences were not significantly different. The endometrium of infertile patients with hydrosalpinx had significantly higher NF KappaB mRNA and protein expression, and significantly lower CFTR and MUC1 mRNA and protein expression, compared to control infertile patients. A positive correlation was observed between CFTR and MUC1 mRNA expression (r = 0.65, P < 0.05); a negative correlation was observed between CFTR mRNA and NF KappaB mRNA expression (r = -0.59, P < 0.05). CONCLUSIONS Increased NF KappaB expression and decreased CFTR and MUC1 expression in the endometrium of infertile patients with hydrosalpinx reinforce the involvement of a molecular mechanism in the regulation of endometrial receptivity.
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Affiliation(s)
- Yong Song
- Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Sichuan, China
| | - Qiushi Wang
- Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Sichuan, China
| | - Wei Huang
- Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Sichuan, China
| | - Li Xiao
- Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Sichuan, China
| | - Licong Shen
- Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Sichuan, China
| | - Wenming Xu
- The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital of Sichuan University, Sichuan, China
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Nimbkar-Joshi S, Katkam RR, Chaudhari UK, Jacob S, Manjramkar DD, Metkari SM, Hinduja I, Mangoli V, Desai S, Kholkute SD, Puri CP, Sachdeva G. Endometrial epithelial cell modifications in response to embryonic signals in bonnet monkeys (Macaca radiata). Histochem Cell Biol 2012; 138:289-304. [DOI: 10.1007/s00418-012-0951-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2012] [Indexed: 10/28/2022]
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Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation. Fertil Steril 2012; 97:1115-23. [PMID: 22425195 DOI: 10.1016/j.fertnstert.2012.02.035] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 01/29/2012] [Accepted: 02/22/2012] [Indexed: 01/26/2023]
Abstract
OBJECTIVE To investigate the role of activin-βA subunit, activin type II receptors, inducible nitric oxide synthase (iNOS), and MUC1 in the pathogenesis of ectopic pregnancy (EP) and their involvement in the determination of the implantation site. DESIGN Observational study. SETTING Academic unit of reproductive and developmental medicine. PATIENT(S) Four women at the luteal phase, three pseudopregnant women at the time of hysterectomy for benign disease, and 10 archived cases of EP. We collected 14 Fallopian tubes were collected from four women at the luteal phase and three pseudopregnant women at the time of hysterectomy for benign disease; specimens from implantation site, trophoblast and remote sites from the implantation site were collected from 10 archived cases of EP. INTERVENTION(S) Immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE(S) Comparison of the expression of candidate molecules between the different groups. RESULT(S) The expression of activin-βA subunit, activin type II receptors, and iNOS was statistically significantly increased and expression of MUC1 statistically significantly decreased in tubes bearing an EP. There was no statistically significant difference in the expression of the candidate molecules between the implantation and remote sites. Candidate molecules were also expressed in the trophoblast. CONCLUSION(S) The pathological expression of candidate molecules by tubes bearing an EP is not involved in the determination of implantation site. Additionally, candidate molecules may play a role in the regulation of trophoblast cells in vivo during early pregnancy.
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Evron A, Goldman S, Shalev E. Effect of primary human endometrial stromal cells on epithelial cell receptivity and protein expression is dependent on menstrual cycle stage. Hum Reprod 2010; 26:176-90. [PMID: 21098625 DOI: 10.1093/humrep/deq296] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Successful implantation requires a receptive endometrium. We hypothesized that effects of endometrial stromal cells (ESC) on epithelial cell receptivity and trophoblast-endometrium interaction are menstrual cycle dependent. METHODS An endometrial in vitro 3D co-culture model of primary human ESC with the endometrial epithelial cell line (RL95-2) was constructed. Co-cultures were prepared using primary ESC from biopsies taken before the window of implantation (ESCbw) and during the window of implantation (ESCw), on cycle days 10-17 and 19-23, respectively. RL95-2 served as a constant parameter upon which the influence of ESC from different phases of the cycle was investigated. proMMP-2 (MMP, matrix metalloproteinase) and proMMP-9 secretion was tested in response to progesterone. Progesterone receptor B (PR-B) and plexin B1 protein expression and mRNA levels were investigated using immunofluorescence and RT-PCR, respectively. RESULTS Progesterone increased proMMP-2 secretion in primary ESCbw (P = 0.0046) but decreased proMMP-2 and proMMP-9 secretion in ESCw (P < 0.0005). In the presence of ESCbw, JAR spheroid attachment rate to overlying RL95-2 cells was decreased (P < 0.0001), whereas in the presence of ESCw, attachment rate was unchanged. Progesterone treatment restored epithelial cell receptivity in co-culture with ESCbw (P = 0.00004). A correlation between spheroid attachment rate and plexin B1 mRNA level was observed (P = 0.01). PR-B protein and mRNA level were influenced by the interplay between RL95-2 and stromal cells. CONCLUSION The effects of human primary ESC on epithelial cell receptivity and trophoblast-endometrium interaction depended upon whether the ESC were taken before or during the window of implantation.
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Affiliation(s)
- A Evron
- Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel
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Jones C, Aplin J, Burton G. First Trimester Histiotrophe Shows Altered Sialylation Compared with Secretory Phase Glycoconjugates in Human Endometrium. Placenta 2010; 31:576-80. [DOI: 10.1016/j.placenta.2010.04.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2010] [Revised: 04/22/2010] [Accepted: 04/26/2010] [Indexed: 11/28/2022]
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Singh H, Nardo L, Kimber SJ, Aplin JD. Early stages of implantation as revealed by an in vitro model. Reproduction 2010; 139:905-14. [DOI: 10.1530/rep-09-0271] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Our limited understanding of the processes underlying steroid hormonal control of human endometrial receptivity is largely due to the lack of a relevant model system. To overcome scarcity of material, we have developed a model in which mouse embryos attach to human Ishikawa cells, which express functional steroid hormone receptors. Blastocysts flushed from day 4 pregnant superovulated mice were transferred to confluent Ishikawa cell monolayers. After 48 h of co-culture, 85% of the blastocysts had attached loosely, but only 40% attached stably to the epithelial cell surface. In contrast, 95% of the embryos attached stably to tissue culture plastic. Thus, weak attachment of a majority of the embryos was followed by stronger adhesion of a smaller proportion. Seventeen percent of the transferred blastocysts modified the epithelial cell surface with loss of MUC1 at the attachment site, extending variably to adjacent epithelial cells. Initially, stable attachment occurred without disruption to the integrity of the epithelial monolayer, but at later stages after the embryo had spread laterally, displacement of subjacent cells was observed. A modest increase in stable attachment, but no changes to MUC1 clearance, was observed after assisted hatching. After 24 h priming of Ishikawa cells by 17β-oestradiol (OE2) followed by 72-h incubation with medroxyprogesterone acetate and OE2, stable attachment increased from 40 to 70%. Initial attachment is efficient either in the presence or in the absence of hormone; steroid treatment increased the incidence of stable attachment. Implantation failure is predicted to occur in this model when embryos fail to progress from initial to stable attachment.
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Shaw JLV, Dey SK, Critchley HOD, Horne AW. Current knowledge of the aetiology of human tubal ectopic pregnancy. Hum Reprod Update 2010; 16:432-44. [PMID: 20071358 DOI: 10.1093/humupd/dmp057] [Citation(s) in RCA: 209] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube. Tubal ectopic pregnancy remains the most common cause of maternal mortality in the first trimester of pregnancy. The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization. This review appraises the data to date researching the aetiology of tubal ectopic pregnancy. METHODS Scientific literature was searched for studies investigating the underlying aetiology of tubal ectopic pregnancy. RESULTS Existing data addressing the underlying cause of tubal ectopic pregnancy are mostly descriptive. There are currently few good animal models of tubal ectopic pregnancy. There are limited data explaining the link between risk factors and tubal implantation. CONCLUSIONS Current evidence supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur. Future studies are needed that address the functional consequences of infection and smoking on Fallopian tube physiology. A greater understanding of the aetiology of tubal ectopic pregnancy is critical for the development of improved preventative measures, the advancement of diagnostic screening methods and the development of novel treatments.
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Affiliation(s)
- J L V Shaw
- Centre for Reproductive Biology, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
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Miller D, Jones C, Aplin J, Nardo L. Altered glycosylation in peri-implantation phase endometrium in women with stages III and IV endometriosis. Hum Reprod 2009; 25:406-11. [DOI: 10.1093/humrep/dep401] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Al-Azemi M, Refaat B, Aplin J, Ledger W. The expression of MUC1 in human Fallopian tube during the menstrual cycle and in ectopic pregnancy. Hum Reprod 2009; 24:2582-7. [DOI: 10.1093/humrep/dep233] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Progesterone induces nano-scale molecular modifications on endometrial epithelial cell surfaces. Biol Cell 2009; 101:481-93. [PMID: 19236310 DOI: 10.1042/bc20080189] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND INFORMATION The endometrial epithelial cell membrane is a key interface in female reproductive biology. Steroid hormones play a predominant role in cyclic changes which occur at this interface during the female menstrual cycle. Specific changes in the morphology of the endometrial epithelial cell surface become apparent with the epithelial transition that drives the switch from a non-receptive to receptive surface due to the action of progesterone on an oestrogen primed tissue. AFM (atomic force microscopy) allows the high-resolution characterization of the endometrial epithelial cell surface. Its contact probe mechanism enables a unique imaging method that requires little sample preparation, yielding topographical and morphological characterization. By stiffening the cell membrane, low concentrations of fixatives allow the surface detail of the cell to be resolved while preserving fine ultra-structural details for analysis. RESULTS In the present study we use high resolution AFM analysis of endometrial epithelial cells to monitor the effect of progesterone on the nanoscale structure of the endometrial cell surface. High-resolution imaging reveals similar topographical nanoscale changes in both the Hec-1-A and Ishikawa model cell lines. Hec-1-B cells, used in the present study as a progesterone receptor negative control, however, exhibit a flattened cell surface morphology following progesterone treatment. Changes in average cell height and surface convolution correlate with increased surface roughness measurements, demonstrating alterations in molecular structure on the cell surface due to hormonal stimulation. CONCLUSIONS Progesterone treatment induces changes to the cell surface as a result of nanoscale molecular modifications in response to external hormonal treatments. AFM provides the basis for the identification, visualization and quantification of these cell surface nanoscale changes. Together these findings demonstrate the utility of AFM for use in reproductive science and cancer biology where it could be applied in both in vitro analysis of protein structure-function relationships and clinical diagnosis.
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Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model. Fertil Steril 2009; 91:256-64. [DOI: 10.1016/j.fertnstert.2007.11.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Revised: 11/06/2007] [Accepted: 11/06/2007] [Indexed: 11/18/2022]
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Fukuda MN, Sugihara K. An integrated view of L-selectin and trophinin function in human embryo implantation. J Obstet Gynaecol Res 2008; 34:129-36. [PMID: 18412772 DOI: 10.1111/j.1447-0756.2008.00776.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Determining molecular mechanisms of human embryo implantation is an extremely challenging task due to the limitation of materials and significant differences underlying this process among mammalian species. Recently, L-selectin and its ligand carbohydrate have been proposed as a system that mediates initial adhesion of human blastocysts to the uterine epithelia. We have also identified trophinin as a unique apical cell adhesion molecule potentially involved in the initial adhesion of trophectoderm of the human blastocyst to endometrial surface epithelia. In the mouse, the binding between ErbB4 on the blastocyst and heparin-binding epidermal growth factor-like growth factor on the endometrial surface enables the initial step of the blastocyst implantation. The evidence suggests that L-selectin and trophinin are included in human embryo implantation. This review summarizes findings relevant to the functions of L-selectin and trophinin in human embryo implantation, and proposes a model that reconciles these cell adhesion mechanisms.
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Affiliation(s)
- Michiko N Fukuda
- Glycobiology Unit, Tumor Microenvironment Program, NCI Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
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Kimber SJ. Blastocyst implantation:the adhesion cascade. REPRODUCTIVE MEDICINE AND ASSISTED REPRODUCTIVE TECHNIQUES 2008. [DOI: 10.3109/9780203091500.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Abstract
Low rates of implantation are an impediment to more efficient assisted reproduction techniques. Improved endometrial receptivity and embryo preparation should lead to higher pregnancy rates, lower rates of early pregnancy failure and fewer multiple pregnancies. As the first site of contact between embryo and endometrium, the luminal epithelium (LE) is responsible for the non-receptive status of proliferative and early secretory tissue, and transformation to receptivity in the mid-secretory phase presumably requires alterations in expression, organization or activation of adhesion systems. Luminal cells are less abundant than their glandular counterparts, and are under-represented in global tissue datasets. Furthermore, alterations in cell surface composition can be readily accomplished by mechanisms that do not rely on altered transcription or translation. Current data from in-vitro models are consistent with initial attachment to mucin in the apical glycocalyx, perhaps via a carbohydrate-mediated interaction, after which the epithelial phenotype is modified by a medium- or short-range embryonic signal. A cascade of interactions follows, mediating embryo migration across the epithelium. Strikingly, numerous potential mediators of adhesion at implantation are located in the lateral rather than the apical surface of LE cells. Attached embryos appear to gain rapid access to this highly adhesive lateral membrane domain.
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Affiliation(s)
- J D Aplin
- Division of Human Development, Medical School, University of Manchester, UK.
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Affiliation(s)
- I K Gipson
- Schepens Eye Research Institute, Boston, MA 02114, USA.
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Abstract
Colonic mucus is a key element of colonic barrier as it is located at the frontier between luminal microflora and colonic mucosa itself. Colonic mucus is mainly composed of high molecular weight glycoproteins called mucins that can be either secreted or membrane-linked. The expression of various colonic mucins is altered in colorectal cancers or inflammations. The aim of this review is to highlight the crucial role played by colonic mucins in the maintenance of colonic barrier integrity, both because they are part of the protective mucus layer, and because they individually exert specific functions involved in epithelial barrier, like cell growth and differentiation, immunomodulation, signal transduction or cell adhesion.
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Affiliation(s)
- Estelle Gaudier
- UMR, Physiologie des Adaptations Nutrionnelles, Centre de recherche en Nutrition Humaine, INRA, 44316 Nantes
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Quezada S, Avellaira C, Johnson MC, Gabler F, Fuentes A, Vega M. Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril 2006; 85:1017-26. [PMID: 16580389 DOI: 10.1016/j.fertnstert.2005.09.053] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2005] [Revised: 09/16/2005] [Accepted: 09/16/2005] [Indexed: 10/24/2022]
Abstract
OBJECTIVE To evaluate gene and protein expression of steroid receptors, nuclear receptor coregulators, and uterine receptivity markers in midsecretory phase endometria from untreated women with polycystic ovary syndrome (PCOS). DESIGN Case-control study. SETTING Hospital research unit. PATIENT(S) Eight patients with PCOS and eight fertile women of similar age to those with PCOS. INTERVENTION(S) Endometrial samples were obtained from women with PCOS (PCOSE) and normal (NE) women during the midsecretory phase of the menstrual cycle. MAIN OUTCOME MEASURE(S) Expression studies (immunohistochemistry, reverse transcription-polymerase chain reaction [RT-PCR] and Western blot). RESULT(S) Endometria from PCOS exhibit higher levels of messenger RNA (mRNA) and protein for estrogen receptor alpha and coactivators than NE. Epithelial cells had a greater expression of progesterone receptor in PCOSE, whereas, no differences were observed in gene and protein expression of the nuclear corepressor (NcoR) and the antiadhesion molecule mucin type-1 (MUC-1) between PCOSE and NE. Immunodetection for the coactivator ARA70 was higher in PCOSE than in NE; in contrast, expression of beta3-integrin in epithelia was lower in PCOSE than in control endometria. CONCLUSION(S) The higher response to steroid hormones of endometria from untreated PCOS-women induces diminished expression of beta3 integrin, which partially explain implantation failure in PCOS patients.
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Affiliation(s)
- Susana Quezada
- Institute of Maternal and Child Research, School of Medicine, San Borja-Arriarán Clinical Hospital, University of Chile, Santiago, Chile
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Guo Q, Tang W, Inagaki Y, Midorikawa Y, Kokudo N, Sugawara Y, Nakata M, Konishi T, Nagawa H, Makuuchi M. Clinical significance of subcellular localization of KL-6 mucin in primary colorectal adenocarcinoma and metastatic tissues. World J Gastroenterol 2006; 12:54-9. [PMID: 16440417 PMCID: PMC4077483 DOI: 10.3748/wjg.v12.i1.54] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess subcellular localization of KL - 6 mucin and its clinicopathological significance in colorectal carcinoma as well as metastatic lymph node and liver tissues.
METHODS: Colorectal carcinoma tissues as well as metastatic lymph node and liver tissues were collected from 82 patients who underwent colorectomy or hepatectomy. Tissues were subjected to immunohistochemical analysis using KL - 6 antibody.
RESULTS: Of the 82 colorectal carcinoma patients, 6 showed no staining, 29 showed positive staining only in the apical membrane, and 47 showed positive staining in the circumferential membrane and/or cytoplasm. Positive staining was not observed in non - cancerous colorectal epithelial cells surrounding the tumor tissues. The five - year survival rate was significantly lower in cases showing positive staining in the circumferential membrane and/or cytoplasm (63.0%) than those showing positive staining only in the apical membrane (85.7%) and those showing no staining (100%). Statistical analysis between clinicopathological factors and subcellular localization of KL - 6 mucin showed that KL - 6 localization in the circumferential membrane and/or cytoplasm was significantly associated with the presence of venous invasion (P = 0.0003), lymphatic invasion (P < 0.0001), lymph node metastasis (P < 0.0001), liver metastasis (P = 0.058), and advanced histological stage (P < 0.0001). Positive staining was observed in all metastatic lesions tested as well as in the primary colorectal carcinoma tissues.
CONCLUSION: The subcellular staining pattern of KL - 6 in colorectal adenocarcinoma may be an important indicator for unfavorable behaviors such as lymph node and liver metastasis, as well as for the prognosis of patients.
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Affiliation(s)
- Qian Guo
- Hepatobiliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113-8655, Japan
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Hebbar V, Damera G, Sachdev GP. Differential expression of MUC genes in endometrial and cervical tissues and tumors. BMC Cancer 2005; 5:124. [PMID: 16188033 PMCID: PMC1249559 DOI: 10.1186/1471-2407-5-124] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2005] [Accepted: 09/27/2005] [Indexed: 02/04/2023] Open
Abstract
Background Mucin glycoprotein's are major components of mucus and are considered an important class of tumor associated antigens. The objective of this study was to investigate the expression of human MUC genes (MUC1, MUC2, MUC5B, MUC5AC and MUC8) in human endometrium and cervix, and to compare and quantitate the expression of MUC genes in normal and cancerous tissues. Methods Slot blot techniques were used to study the MUC gene expression and quantitation. Results Of the five-mucin genes studied, MUC1, MUC5B and MUC8 showed high expression levels in the normal and cancerous endometrial and cervical tissues, MUC2 and MUC5AC showed considerably lower expression. Statistically, higher levels of MUC1, MUC5B and MUC8 were observed in endometrial adenocarcinomas compared to normal tissues. In contrast, only MUC1 levels increased with no significant changes in expression of MUC5B and MUC8 in cervical tumors over normal cervical tissues. Conclusion Endometrial tumors showed increased expression of MUC1, MUC5B and MUC8 over normal tissues. Only MUC1 appears to be increase, in cervical tumors. All the studied tissues showed high and consistent expression of MUC8 mRNA. Low to neglible levels of MUC2 and MUC5AC were observed in all studied endometrial and cervical tissues.
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Affiliation(s)
- Vidya Hebbar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190, USA.
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Dominguez F, Yáñez-Mó M, Sanchez-Madrid F, Simón C. Embryonic implantation and leukocyte transendothelial migration: different processes with similar players? FASEB J 2005; 19:1056-60. [PMID: 15985528 DOI: 10.1096/fj.05-3781hyp] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
A clear parallelism between the different steps in human embryo-endometrial apposition/adhesion/invasion and leukocyte-endothelium rolling/adhesion/extravasation can be established. During human implantation and leukocyte trafficking, a first wave of soluble mediators regulates the expression and functional activity of adhesion molecules such as L-selectin and integrins, which mediate both processes. Apical surfaces of human endometrial epithelium and endothelium are key elements for the initiation of molecular interactions to capture the blastocyst or leukocyte, respectively. Subsequently, the blastocyst and the leukocyte migrate through the epithelium and endothelium toward their final destination, the endometrial stroma, to initiate placentation or the inflammatory foci as part of the immune response. Similarities between the intermediate molecular mechanisms of these two physiologically unrelated processes are discussed.
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Affiliation(s)
- F Dominguez
- Instituto Valenciano de Infertilidad Foundation (FIVI), Valencia University, Valencia, Spain
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Emiliani S, Delbaere A, Devreker F, Englert Y. Embryo-maternal interactive factors regulating the implantation process: implications in assisted reproductive. Reprod Biomed Online 2005; 10:527-40. [PMID: 15901462 DOI: 10.1016/s1472-6483(10)60831-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The embryo-maternal dialogue that starts very early in the life of the embryo is crucial for its own implantation. A disturbance in this dialogue is the major reason for which 60% of all pregnancies are terminated at the end of the periimplantation period. Many studies have been performed to improve the understanding of the molecular mechanisms involved in this dialogue. Both partners, the mother and the embryo, are equally involved in this exchange of signals. Much progress has been done in understanding the role of (i) chorionic gonadotrophin, (ii) growth factors and cytokines, and (iii) steroid hormones and other mediators, produced either by the embryo, by the mother, or by both, during the peri-implantation period. Today it is clear that their production dictates changes in the endometrium, in the immunological system of the mother and in embryo metabolism, that enable the embryo to implant. Knowledge of the molecular mechanisms involved in the embryo-maternal interaction are reviewed in this article.
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Abstract
Implantation is an intricately timed event necessary in the process of viviparous birth that allows mammals to nourish and protect their young during early development. Human implantation begins when the blastocyst both assumes a fixed position in the uterus and establishes a more intimate relationship with the endometrium. Due to the impracticalities of studying implantation in humans, animal models are necessary to decipher the molecular and mechanical events of this process. This review will discuss the differences in implantation between different animal models and describe how these differences can be utilized to investigate discrete implantation stages. In addition, factors that have been shown to be involved in implantation in the human and other various animal models including growth factors, cytokines, modulators of cell adhesion, and developmental factors will be discussed, and examples from each will be given.
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Affiliation(s)
- Kevin Y Lee
- Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030-3498, USA
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Abstract
Implantation is a complex process that requires synchronization between the embryo and a receptive endometrium. Hormones, such as the female sex steroids, prostaglandins, and peptide hormones, regulate the cellular and molecular mediators of endometrial receptivity, which include pinopodes, cell adhesion molecules, cytokines, homeobox genes, and growth factors. These mediators can be altered, despite the presence of normal hormone levels and endometrial histology; this limits the usefulness of the luteal phase endometrial biopsy. Therefore, analysis of markers of endometrial receptivity may predict successful implantation better. Elevated androgen and estrogen levels, as seen with polycystic ovary syndrome and controlled ovarian hyperstimulation, respectively, also can have detrimental effects on the endometrium, and therefore, implantation.
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Affiliation(s)
- Pinar H Kodaman
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Abstract
Implantation is a phenomenon that involves an interaction between the embryo and maternal endometrium. There is, in the menstrual cycle, a short and precise period of time in which the maternal-embryonic interaction is optimal and culminates with adhesion and invasion of the blastocyst into the progesterone-induced secretory endometrium. This period is called nidation or implantation window. In the implantation window changes occur in endometrial epithelial morphology, characterized by the appearance of membrane projections called pinopodes. Pinopodes are progesterone-dependent organelles, that look like apical cellular protrusions appearing between days 20 and 21 of the natural menstrual cycle. There are many factors that regulate the changes typical of the implantation window and the appearance of the pinopodes. The embryonic and maternal expression of growth factors and cytokines, calcitonin, HOX genes and cell adhesion molecules might all play a major role in the phenomenon of implantation. The cytokines function as chemical messengers and can serve as biomarkers of uterine receptivity. Understanding the function of these biomarkers and their role in determining the implantation window in women, will help us to diagnose and treat infertile couples more efficiently.
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Affiliation(s)
- M Cavagna
- Department of Gynecology and Obstetrics, Santo Amaro University (UNISA) School of Medicine, Rua Viradouro 58, 04538-110 São Paulo, Brazil.
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Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PGA. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online 2004; 9:692-715. [PMID: 15670421 DOI: 10.1016/s1472-6483(10)61781-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A pregnancy rate of approximately 15% per cycle renders the process of human reproduction inefficient. The cycle-dependent expression of molecules involved in the embryo-endometrial dialogue has lead to the identification of a 'window of implantation'. This is the unique temporal and spatial expression of factors that allows the embryo to implant (via signalling, appositioning, attachment and invasion) in a specific time frame of 48 h, 7-10 days after ovulation. Integrin molecules, L-selectin ligands, mucin-1, heparin-binding epidermal growth factor and pinopodes are involved in appositioning and attachment. The embryo produces cytokines and growth factors [interleukins, prostaglandins, vascular endothelial growth factor (VEGF)] and receptors for endometrial signals (leukaemia inhibitory factor receptor, colony stimulating factor receptor, insulin-like growth factors and heparin binding epidermal growth factor receptor). The immune system plays an important role. Immunomodulatory factors such as glycodelin, inhibin and interleukin prevent a graft-versus-host reaction. Angiogenesis controlled by VEGF and prostaglandins is needed for formation of a receptive endometrium and a placenta. Identification of these factors has led to their use as markers of implantation that may identify defects causing subfertility. An ideal marker of implantation is sensitive and specific, and easy to obtain without disturbing implantation. Glycodelin and leukaemia inhibitory factor (serum) and integrins and pinopodes (biopsies) are promising candidates.
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Affiliation(s)
- Diederik A Hoozemans
- VU University Medical Centre Amsterdam, IVF-Centrum, Poli Zuid, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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Abstract
PURPOSE To determine the expression of MUC1 in the human corneal endothelium. METHODS Reverse transcription-polymerase chain reaction (RT-PCR) for MUC1 was performed with total RNA from endothelial cells extracted from the human cornea. In situ hybridization with sense and antisense probes of human MUC1 was performed on the human corneal endothelium, immunoblot analysis using monoclonal antibody specific for human MUC1 (HMFG-1, or VU4H5) was performed on collected human corneal endothelial cells, and immunohistochemistry on the human cornea, using the same antibodies. RESULTS MUC1 mRNA expression was observed by RT-PCR in the human corneal endothelium, and the nucleotide sequence from the amplified band was matched with known human MUC1. In situ hybridization studies showed the localization of MUC1 mRNA in the human corneal endothelium, and immunoblot assay demonstrated the presence of MUC1 protein (MW > 200 kd). In addition, MUC1 protein was observed on the apical surface of cells and at the superficial layer of the cytoplasm in immunohistochemical studies. CONCLUSIONS Human corneal endothelial cells produce MUC1, which is known to have protective and lubricative roles.
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Affiliation(s)
- Seung Eun Jung
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science, Seoul
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Lindhard A, Bentin-Ley U, Ravn V, Islin H, Hviid T, Rex S, Bangsbøll S, Sørensen S. Biochemical evaluation of endometrial function at the time of implantation. Fertil Steril 2002; 78:221-33. [PMID: 12137855 DOI: 10.1016/s0015-0282(02)03240-5] [Citation(s) in RCA: 106] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVE To review the literature on various endometrial factors assumed to be of importance to implantation and to evaluate their potential clinical value in the assessment of endometrial function at the time of implantation in infertile women in natural and stimulated cycles. DESIGN Literature review. RESULT(S) Cytokines such as leukemia inhibitory factor, colony-stimulating factor-1, and interleukin-1 have all been shown to play important roles in the cascade of events that leads to implantation. They participate in a synchronized cooperation between the endometrium and the preimplanting embryo under the influence of steroid hormones. The same applies to the integrin alpha(v)beta(3), glycodelin, and the polymorphic mucin 1. The usefulness of these factors to assess endometrial receptivity and to estimate the prognosis for pregnancy in natural and artificial cycles remains to be proven. CONCLUSION(S) The studies performed to date have mostly included only small groups of patients with a lack of fertile controls, and only a few prospective, controlled trials have been carried out. Therefore, definite conclusions about the clinical value of these factors in the assessment of endometrial function and prognosis for pregnancy after artificial reproductive therapy cannot be drawn at present. Further evaluation of their importance for and function during implantation is needed.
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Affiliation(s)
- Anette Lindhard
- Fertility Clinic, Juliane Marie Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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Abstract
We know that the implantation process requires a functionally normal embryo at the blastocyst stage and a receptive endometrium, but also a communication link between them is needed. This paracrine dialogue between the embryo, endometrium and the corpus luteum are known to occur in ruminants and primates, more specifically endometrial-embryonic interactions have been reported in rodents and primates but not in humans. This process is a highly regulated mechanism and many molecules take part in this cross-talk. Here, we present updated information in humans on the embryonic regulation of endometrial epithelial molecules such as chemokines, adhesion and anti-adhesion molecules, and leptin during the apposition and adhesion phases of human implantation.
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Affiliation(s)
- F Dominguez
- Fundación Instituto Valenciano de Infertilidad para el Estudio de la Reproducción Humana, Guardia Civil 23, 46020 Valencia, Spain
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Abstract
The endometrium has been conventionally studied using histologic criteria. Our understanding of endometrial physiology has been advanced tremendously by research into the molecules that mediate its development and function. These molecules demonstrate a dynamic expression pattern through the menstrual cycle and have been implicated in endometrial growth, differentiation, and receptivity. These molecules include secreted proteins (endometrial bleeding-associated factor, glycodelin-A, insulin-like growth factor binding protein-1), cell-surface receptors (integrins), and nuclear transcription factors (HOXA10 and HOXA11). The homeobox genes Hoxa10 and Hoxa11 are necessary for implantation because mice with mutations in these genes exhibit a failure of implantation. HOXA10 and HOXA11 have been shown to be important for implantation in humans as well. Knowledge of endometrial molecular dynamics may now be used to enhance our ability to diagnose implantation defects. It may soon be possible to treat individual molecular defects by protein supplementation or gene therapy.
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Affiliation(s)
- G S Daftary
- Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA
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DeSouza MM, Surveyor GA, Price RE, Julian J, Kardon R, Zhou X, Gendler S, Hilkens J, Carson DD. MUC1/episialin: a critical barrier in the female reproductive tract. J Reprod Immunol 1999; 45:127-58. [PMID: 10674981 DOI: 10.1016/s0165-0378(99)00046-7] [Citation(s) in RCA: 100] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The female reproductive tract must resist microbial infections as well as support embryonic development, implantation and placentation. Reproductive tract mucins, in general, and Muc1/episialin, in particular, play key roles in implantation related events and in protection from microbial infection. High levels of mucin expression in the lower reproductive tract presumably affords protection against infection while down-regulation of uterine mucins has been suggested to provide access to the uterine surface. The present studies demonstrate that mucins, particularly Muc1, are effective barriers to embryo attachment. Furthermore, a strain of female Muc1 null mice in normal housing displays chronic infection and inflammation of the lower reproductive tract and markedly reduced fertility rates. This phenotype is not observed when Muc1 nulls are housed in a pathogen-free environment indicating that this phenotype results from chronic microbial exposure. Only normal endogenous flora were isolated from the reproductive tracts of affected Muc1 null mice, suggesting that these bacterial species become opportunistic with loss of the mucin barrier. Staphylococcal adherence to lower reproductive tract epithelia was found to be mediated by cell surface mucin carbohydrates. Collectively, these studies demonstrate a critical barrier role for Muc1 in various aspects of female reproductive tract physiology.
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Affiliation(s)
- M M DeSouza
- Department of Biological Sciences, University of Delaware, Newark 19716-2590, USA
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Habiba MA, James RF, Bell SC, Al-Azzawi F. Identification of a cycle-modulated 200-kDa endometrial antigen by a monoclonal antibody LDS60. J Immunol Methods 1999; 227:65-73. [PMID: 10485255 DOI: 10.1016/s0022-1759(99)00070-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We have developed a mouse monoclonal antibody, LDS60, against a cycle-dependent antigen by immunising (MF1 x BALB/c)F1 mice with a human endometrial membrane preparation. In formalin fixed paraffin embedded sections, LDS60 identified an epithelial specific antigen which exhibited a specific pattern of expression during the menstrual cycle. It was only occasionally expressed during the proliferative phase. During the early-secretory phase, there was intracytoplasmic staining in about half of the glands examined. This was in the form of small microvesicles, either near the base of the cell or supranuclear. In the mid-secretory phase the same proportion of glands exhibited staining in the form of micro-vesicles that were noted to accumulate nearer to the cell apices. In the late-secretory phase, there was no intracytoplasmic staining and the antigen was localised to the luminal border of the glandular epithelium and some staining appeared within the gland lumen of approximately 20% of glands. It is also diffusely expressed in some mucous secreting cells in the tongue, stomach and colon, as well as lung pneumocytes. The antigen has a molecular weight of approximately 200 kDa as identified by immunoblotting. This antigen exhibits similarities to MUC-1 which is involved in uterine receptivity and could therefore have a similar role. Its cycle modulation suggests that it could be used to monitor the uterine response to steroids.
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Affiliation(s)
- M A Habiba
- Department of Obstetrics and Gynaecology, Leicester University School of Medicine, UK
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Bon GG, Kenemans P, Dekker JJ, Hompes PG, Verstraeten RA, van Kamp GJ, Schoemaker J. Fluctuations in CA 125 and CA 15-3 serum concentrations during spontaneous ovulatory cycles. Hum Reprod 1999; 14:566-70. [PMID: 10100011 DOI: 10.1093/humrep/14.2.566] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The aim of this study was to investigate cycle dependent changes of serum CA 125 and CA 15-3 concentrations during spontaneous ovulatory cycles. Twenty apparently healthy women with spontaneous menstrual cycles attending our infertility clinic were included. Of these women, 18 had occluded tubes as a result of sterilization. Ovulation was confirmed by luteinizing hormone test and ultrasonography and, to exclude endometriosis, a laparoscopy was performed. Serum samples for CA 125, CA 15-3, 17 beta-oestradiol and progesterone determinations were taken every second day starting on the 2nd day of the cycle until the 7th day of the next cycle. After correction for inter-individual variation in serum concentrations, highest CA 125 concentrations were found during the menstruation. During the follicular and peri-ovulatory phase CA 125 serum concentrations were lowest. For CA 15-3, serum concentrations were not statistically different throughout the cycle. CA 125 and oestradiol concentrations were negatively correlated, CA 15-3 and oestradiol concentrations were positively correlated. Absolute serum concentrations of both CA 125 and CA 15-3 vary among females. Within the female, fluctuations of CA 125 are phase related. In the population studied most of the patients had tubal obstruction and high CA 125 serum concentrations during menstruation, which revokes the theory that the menstrual rise of CA 125 is due only to retrograde menstruation.
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Affiliation(s)
- G G Bon
- Department of Obstetrics and Gynaecology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
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Agrawal B, Gendler SJ, Longenecker BM. The biological role of mucins in cellular interactions and immune regulation: prospects for cancer immunotherapy. MOLECULAR MEDICINE TODAY 1998; 4:397-403. [PMID: 9791863 DOI: 10.1016/s1357-4310(98)01322-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Among the human mucins, MUC1 is unique in its cell-surface transmembrane expression and its apparent signal-transduction functions. The high expression of MUC1 on many human cancers makes it an attractive target for immunotherapy. Immunization of human cancer patients with MUC1 peptides has resulted in the generation of both anti-MUC1 antibody and cytotoxic T lymphocyte responses. Recently, a novel immunoregulatory role for MUC1 has been suggested by experiments demonstrating that soluble MUC1 induces T-cell unresponsiveness, and that T cells appear to express and secrete MUC1 following their activation. MUC1 is an apparent paradox, having both adhesive and antiadhesive functions, and immunostimulatory and immunosuppressive activities.
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Affiliation(s)
- B Agrawal
- Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, AZ 85259, USA
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Jones DT, Monroy D, Ji Z, Pflugfelder SC. Alterations of ocular surface gene expression in Sjögren's syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1998; 438:533-6. [PMID: 9634933 DOI: 10.1007/978-1-4615-5359-5_75] [Citation(s) in RCA: 79] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We have demonstrated that conjunctival epithelium of SS patients displays increased numbers of S-phase cells compared with non-dry eye controls. Moreover, in SS patients, these S-phase cells are distributed throughout all strata of the epithelium. The expression of MUC-1, a cell surface marker indicative of terminally differentiated epithelium, is localized to the conjunctival epithelial surface in SS and control patients. However, MUC-1 surface immunoreactivity appears to be reduced in SS epithelium, suggesting disruption of normal epithelial differentiation. A MUC-1 epitope exposed by pretreatment with neuraminidase is expressed in the basal and suprabasal layers of both patient populations. This antigen likely represents nascent, partially processed MUC-1(6) and may serve as a marker of the preterminally differentiated epithelial phenotype. Messenger RNA encoding several different inflammatory cytokines, including TNF-alpha, IL-1 alpha and beta, IL-6, IL-8, IL-10, and TGF-beta 1, is expressed at elevated levels within the conjunctival epithelium of SS patients compared with non-dry eye controls. Based on these observations, we have formulated a model to explain the ocular surface pathology of Sjögren's syndrome. We hypothesize that mechanical abrasion secondary to aqueous tear deficiency creates an inflammatory environment where conjunctival epithelial cells and lymphocytes are stimulated to produce and secrete various cytokines (i.e., IL-1, TNF-alpha, IL-6, IL-8, etc.) into the tear film. Elevated cytokine levels within the tear film, perhaps combined with reduced concentrations of essential lacrimal gland-derived factors (i.e., EGF, retinol), create an environment in which terminal differentiation of the ocular surface epithelium is impaired. As a consequence, the epithelium becomes hyperplastic, displaying increased mitotic activity, and loses the ability to express mature protective surface molecules including the membrane-bound mucin, MUC-1. This would imply that anti-inflammatory medications (i.e., corticosteroids or cyclosporine) that suppress the inflammatory component of this cascade may ameliorate the ocular surface disease and discomfort experienced by SS patients.
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Affiliation(s)
- D T Jones
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida, USA
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Abstract
PROBLEM This study investigated how pregnancy might protect against breast cancer. METHOD OF STUDY A critical review of the literature was done. RESULTS/CONCLUSIONS Support for an active role in pregnancy immunizing against breast cancer comes from case studies demonstrating a reciprocal correlation between pregnancy and breast cancer as well as recent experiments supporting the fetal antigen hypothesis that confirms the presence of a tumor-specific antigen, MUC1, on both fetal and breast cancer tissues. Multiparous women also generate anti-MUC1 major histocompatibility complex-restricted cytotoxic T cell cytolytic activity against MUC1-bearing tumor cell lines. Careful investigation of the fetal antigen hypothesis and tolerogenic mechanisms may lead to effective vaccination protocols against breast cancer and other cancers.
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Affiliation(s)
- F Botelho
- Department of Pathology, McMaster University, Hamilton, Ontario, Canada
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Lapensée L, Paquette Y, Bleau G. Allelic polymorphism and chromosomal localization of the human oviductin gene (MUC9). Fertil Steril 1997; 68:702-8. [PMID: 9341614 DOI: 10.1016/s0015-0282(97)00317-8] [Citation(s) in RCA: 116] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To determine if the gene coding for human oviductin (the estrogen-dependent, oviduct-specific glycoprotein with an affinity for the zona pellucida) shows length polymorphism in the region of tandem repeats. To determine the frequencies of the length alleles in health and disease. DESIGN Descriptive fundamental and clinical studies. SETTING Fertility clinic and research center, university teaching hospital. PATIENT(S) Fertile women, women with a history of ectopic pregnancy or tubal disease, and women with stage I or II endometriosis. INTERVENTION(S) Blood samples were drawn for DNA analysis. MAIN OUTCOME MEASURE(S) Length and sequence of the region of tandem repeats. RESULT(S) Four different length alleles of the human oviductin gene were identified. Their relative frequencies in pathologic cases were not statistically significant compared with those found in normal fertile women. The human genome contains a single copy of the oviductin gene located on chromosome 1p13. CONCLUSION(S) The human oviductin gene codes for a glycoprotein that shares the characteristics of epithelial mucins. Because eight epithelial mucin genes have been identified so far, we therefore propose to name this gene MUC9. The biologic function of the protein is likely to include protection of the early embryo and of the fallopian tube itself.
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Affiliation(s)
- L Lapensée
- Maisonneuve-Rosemount Research Center, Université de Montréal, Québec, Canada
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Affiliation(s)
- J D Aplin
- Department of Obstetrics and Gynaecology, University of Manchester, UK
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Aplin JD, Hey NA, Li TC. MUC1 as a cell surface and secretory component of endometrial epithelium: reduced levels in recurrent miscarriage. Am J Reprod Immunol 1996; 35:261-6. [PMID: 8962658 DOI: 10.1111/j.1600-0897.1996.tb00042.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The mucin MUC1 is a large, highly glycosylated, hormonally regulated product of endometrial glandular and luminal epithelium with both cell surface-associated and secreted isoforms. The abundance of mRNA coding for MUC1 increases about sixfold from the proliferative to the early secretory phase (Hey et al., J. Clin. Endocrinol. Metab. 78:337-342, 1994). Immunohistochemical studies show intracellular deposits accumulating in the early secretory phase followed by the release of MUC1 into gland lumens. The apical surface of luminal epithelium is strongly immunopositive in the early secretory phase. We have used a two site ELISA to measure MUC1 in uterine flushings as a function of time after the luteinising hormone (LH) peak. Low levels of secretory MUC1 are observed before day LH+7, while values on days LH+7-LH+13 are much higher. Using semi-quantitative immunohistochemical methods we have shown that in women suffering recurrent spontaneous miscarriage, mid secretory phase levels of MUC1 core protein and mucin-associated glycans are reduced (Serle et al., Fertil. Steril. 62:989-996, 1994). Similarly, lower core protein levels are observed in uterine flushings after day LH+7 in these women. Reduced epithelial secretory function and a resultant change in uterine fluid composition are features of endometrium from recurrent miscarriage patients.
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Affiliation(s)
- J D Aplin
- Department of Obstetrics and Gynaecology, University of Manchester, U.K
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Patton S, Gendler SJ, Spicer AP. The epithelial mucin, MUC1, of milk, mammary gland and other tissues. BIOCHIMICA ET BIOPHYSICA ACTA 1995; 1241:407-23. [PMID: 8547303 DOI: 10.1016/0304-4157(95)00014-3] [Citation(s) in RCA: 189] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
MUC1 is a mucin-type glycoprotein that is integrally disposed in the apical plasma membrane of the lactating epithelial cell and protrudes from the cell surface into the alveolar lumen where milk is stored. Envelopment of milk fat globules by this membrane accomplishes their secretion and conveys MUC1 into milk. The human form of this mucin has been detected in many other organs, tissues and body fluids. It projects from the cell surface as long filaments. In the human and a number of other species, MUC1 is polymorphic due to variable numbers of a tandemly repeated segment 20 amino acids in length. The individual codominantly expresses two alleles for the mucin so that differences in its size among individuals and between the two forms of an individual are observed. The tandem repeats are rich in serines and threonines which serve as O-glycosylation sites. Carbohydrate content of MUC1, as isolated from milk of human, bovine and guinea pig, is approximately 50%. The oligosaccharides carry substantial sialic acid at their termini and this accounts for two putative functions of this mucin, i.e., to keep ducts and lumens open by creating a strong negative charge on the surface of epithelial cells which would repel opposite sides of a vessel, and to bind certain pathogenic microorganisms. MUC1 is protease resistant (trypsin, chymotrypsin and pepsin) and large fragments of it can be found in the feces of some but not all breast-fed infants. MUC1 has a highly varied structure because of its polymorphism, qualitative and quantitative variations in its glycosylation between tissues, individuals and species, and differences due to divergence in the nucleotide sequences among species. Sequencing of the MUC1 gene for various species is showing promise of revealing unique evolutionary relationships and has already indicated conserved aspects of the molecule that may be functionally important. Among these are positions of serine, threonine and proline in the tandem repeats and a high degree of homology in the transmembrane and cytoplasmic segments of the molecule.
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Affiliation(s)
- S Patton
- Department of Neurosciences, University of California San Diego, La Jolla 92093, USA
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Finn OJ, Jerome KR, Henderson RA, Pecher G, Domenech N, Magarian-Blander J, Barratt-Boyes SM. MUC-1 epithelial tumor mucin-based immunity and cancer vaccines. Immunol Rev 1995; 145:61-89. [PMID: 7590831 DOI: 10.1111/j.1600-065x.1995.tb00077.x] [Citation(s) in RCA: 184] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Many obstacles still stand in the way to eliciting an effective immune response against cancer, even though several antigens and antigenic peptides have been identified as potential tumor targets. All of them, including the MUC-1 mucin, share the caveat of being normal cellular proteins. Unlike all the others, however, MUC-1 expressed on tumors can still be considered a truly tumor-specific antigen. Its expression on normal cells is hidden from the immune system, and its aberrant glycosylation on tumors creates new epitopes recognized by the immune system. Moreover, all other tumor targets identified so far are MHC-restricted peptides that can only be recognized by patients who carry a specific HLA type, or on tumors which continue to express particular HLA alleles. MUC-1 is powerfully different. Recognized as a native molecule independent of MHC, it is a universal immunogen and a universal target, and if made effectively immunogenic, it would be expected to elicit immune responses in all patients, and against numerous MUC-1 expressing human tumors. It may, in fact, be the extraordinary solution to an extraordinary problem of cancer immunity and immunotherapy.
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Affiliation(s)
- O J Finn
- Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA
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Aplin JD, Seif MW, Graham RA, Hey NA, Behzad F, Campbell S. The endometrial cell surface and implantation. Expression of the polymorphic mucin MUC-1 and adhesion molecules during the endometrial cycle. Ann N Y Acad Sci 1994; 734:103-21. [PMID: 7978908 DOI: 10.1111/j.1749-6632.1994.tb21739.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The cell surface mucin MUC-1 is present in endometrial epithelial cells and their associated apical glycocalyx and is also released into gland lumens as a secretory product. MUC-1 mRNA and core protein are found at low levels in the proliferative phase of the cycle, but their abundance increases after ovulation. Endometrial MUC-1 has been found to carry sialokeratan sulphate chains and these show a dramatically increased abundance in cells and secretions in the post-ovulatory phase of the cycle, reaching a maximum in secretions 6-7 days after the LH peak. The apical epithelium also contains adhesion receptor molecules of the integrin and CD44 families. MUC-1 is large and highly glycosylated and probably extends farther from the cell surface than these 'conventional' glycoprotein receptors. It has the potential to inhibit sterically receptor-mediated cell-cell adhesion. However, it is also possible that MUC-1 displays specific (e.g., glycan) recognition structures for the initial attachment of the blastocyst or that the embryo may create a specialised microenvironment in which to implant.
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Affiliation(s)
- J D Aplin
- Department of Obstetrics and Gynaecology, University of Manchester, U.K
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