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PubMed1989

Gestational trophoblastic disease in New Zealand, 1980-1986.

During the period 1980 to 1986, inclusive, 350 cases of gestational trophoblastic disease were recorded within New Zealand; of these cases nearly 70% were reported to a Register established to obtain epidemiological information. Clinical information obtained with the notifications revealed no difference in incidence of gestational trophoblastic disease among the 3 main ethnic groups which make up the New Zealand population; the uterine fundus was recorded as being large for dates in only 26%; the most common clinical presentation was as a threatened abortion; 7% of the cases were diagnosed at either routine ultrasound examination or at termination of pregnancy, there having been no suspicions prior to that procedure. A review of histological material obtained following notification suggested that the histological diagnosis of trophoblastic disease could not be substantiated in 14.7% of cases. During the period under review, therefore, there were 299 cases of trophoblastic disease (all but 2 of which were hydatidiform mole) and 447,667 pregnancies giving an incidence of 1 case of trophoblastic disease per 1,497 pregnancies.

Adult↗
PubMed1988

Isolation and characterization of rat trophoblast cells.

Previous immunohistochemical studies of the rat placenta using specific alloantisera and/or monoclonal antibodies showed that the basal zone trophoblasts stained for Pa and Aa class I major histocompatibility complex (MHC) antigens and for the human SP1-related antigen. In an effort to isolate the basal zone trophoblast cells from the rat placenta, we used these markers to assess the degree of purification of the cells separated by density gradient centrifugation using either Ficoll-Hypaque or Percoll as the gradient medium. The cells were put either on the top or at the bottom of discontinuous density gradients in the range of 1.005-1.10 g/ml. The cell separation profiles for the two media were different. With Percoll, most of the trophoblast cells (80-95%) were collected at the density gradients 1.04/1.06 and 1.06/1.08, whereas with Ficoll-Hypaque, these gradients separated only a small fraction (4-23%) of the trophoblast cells, and most of them pelleted at the bottom of the tube. The trophoblast cells separated by Ficoll-Hypaque, however, showed fewer contaminant cells than those separated by the Percoll gradients.

Animals↗
PubMedDate not supplied

Expression of epidermal growth factor receptor and transferrin receptor by human trophoblast populations.

Epidermal growth factor (EGF) has several roles, including stimulation of cell division and differentiation. EGF receptor (EGFR) has been localized to villous syncytiotrophoblast, but expression by other human trophoblast populations has not been reported. EGFR expression was examined in normal and pathological placental tissues using a streptavidin-biotin-peroxidase technique; results were compared with expression of transferrin receptor (Tf-R) in similar tissues. EGFR was detected on villous syncytiotrophoblast in early and term pregnancy with labelling of the apical membrane, focal cytoplasmic reactivity, and patchy labelling of the trophoblast basement membrane. In contrast with other reports, EGFR was also consistently localized to villous cytotrophoblast, chorion laeve, and extravillous trophoblast populations in maternal uterine tissues. Maternal decidua showed diffuse labelling of stromal cells, particularly in the superficial zones. The reaction pattern in ectopic tubal pregnancy was similar to that in early intrauterine pregnancy. In molar pregnancy, EGFR was detected on villous syncytiotrophoblast and cytotrophoblast. In contrast, in normal, ectopic, and molar pregnancies labelling for Tf-R was confined to syncytiotrophoblast and to the proximal portions of the cytotrophoblast columns. Expression of EGFR by all trophoblast cells may represent a mechanism of placental growth and proliferation control. EGFR may also be involved with establishment of differentiated trophoblast functions including hormone secretion.

Antibodies, Monoclonal↗
PubMedDate not supplied

Major histocompatibility complex class I antigens expressed on rat trophoblast cells.

There is controversy about the size of the major histocompatibility complex antigens of trophoblast cells from placenta. There are some reports that the heavy chains of these molecules are smaller (39-43 kd) than those of the classical class I antigens (45-46 kd), while there are others which show that both the light and the heavy forms of class I antigens occur in the trophoblast cells. In order to investigate this problem, we studied the classical class I antigen (RT1.Aa) and the pregnancy-associated class I antigen (Pa) of the rat from 125I-labeled basal trophoblast cells, isolated from the placenta of WF females pregnant by DA males, using very mild conditions. These antigens were compared with those of the syngeneic (DA x DA) trophoblast cells or paternal (DA) lymphocytes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Both the Aa and Pa antigens, precipitated from the two trophoblast preparations, showed a heavy chain of 46 kd associated with a 12 kd beta 2-microglobulin component, as did the same molecules precipitated from the lymphocytes. Heavy chains in the range of 39-43 kd could not be detected in any of the samples. The results suggest that the smaller molecular weight heavy chains are methodological artifacts and could arise from loss of a glycan(s) during isolation.

Animals↗
PubMed1991

Analysis of the expression and immunostimulatory capacity of class I major histocompatibility antigens on rat trophoblast cell lines.

In rat strains expressing the a and other major histocompatibility complex (MHC) haplotypes, subpopulations of placental trophoblast cells synthesize the nonclassical class I Pa antigen in preference to the classical RT1.Aa antigen. In this study, a rat trophoblast cell line, R8RP.3, which was derived from midgestation placentas of PVG.R8 (RT1.Aa) rats, was shown to express class I antigens similarly to those of trophoblast cells in situ. Both unstimulated and IFN-gamma-exposed metabolically labeled R8RP.3 cells synthesized more Pa than RT1.Aa antigen. The reverse was true for labeled spleen cells from PVG.R8 rats. The R8RP.3 cells failed to stimulate allogeneic lymphocyte proliferation even when high levels of both classical and nonclassical class I MHC antigens were expressed on their membranes after incubation with IFN-gamma. These experiments thus supply the first evidence that the inductive phase of the immune response is not promoted by trophoblast cell class I MHC antigens, which could explain the failure of mothers to mount immune responses to class I MHC positive trophoblast cells.

Animals↗
PubMed1995

Alloantibody responses to antigens recognized by rabbit antitrophoblast antisera in trophoblast and mononuclear cell (MNC) membranes by primary aborting women before and after paternal leukocyte immunization.

PROBLEM: Because shared allogeneic antigens are expressed on peripheral blood lymphocytes, as well as trophoblasts, it has been proposed that lymphocyte transfusions may appropriately sensitize recurrent spontaneous aborters (RSA) to trophoblast and lead to pregnancy conservation. The degree to which these responses are affected by this treatment, however, has not been defined. METHOD: SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analyses were used to study the alloantibody responses in RSA patients both before and after immunization with paternal leukocytes (MNC) against membrane proteins isolated from peripheral blood mononuclear cells (MNC), first trimester and full term chorionic villi (CV). RESULTS: A distinct set of antigens with apparent molecular weights of 32, 36, 41, 63, 65, and 85 kDa was identified in both MNC and trophoblast membranes by rabbit anti-trophoblast antisera. In addition, a 55 kDa protein was recognized by MNC membranes. Thirty-eight percent of primary RSA sera recognized this 55 kDa protein. After paternal MNC immunization, all primary RSA samples displayed increased reactivity or produced antibodies to this 55 kDa protein when compared with preimmunization sera. The protein was identified as MCP using a rabbit polyclonal anti-MCP antisera. In contrast, reactivity to the other antigens present in the membrane preparations decreased after paternal MNC immunization. CONCLUSION: Changes in immune reactivity in RSA patients after paternal MNC immunization suggest that immunization alters serum immune reactivity to MNC and trophoblast shared antigens.

Abortion, Habitual↗
PubMed1996

Altered expression of human leukocyte antigen G (HLA-G) on extravillous trophoblasts in preeclampsia: immunohistological demonstration with anti-HLA-G specific antibody "87G" and anti-cytokeratin antibody "CAM5.2".

PROBLEM: Human leukocyte antigen-G (HLA-G) is suggested to be at play in the materno-fetal immune relationship during pregnancy. In the light of current concept that disruption of the materno-fetal immune relationship could account for several complications of pregnancy, including preeclampsia, we asked whether the expression of HLA-G protein on the trophoblasts is altered in preeclampsia. METHOD: The presence of HLA-G protein in the extravillous trophoblasts in placenta obtained from five preeclamptic patients and seven uncomplicated pregnant women was determined by means of an immunohistochemical technique. RESULTS: All of the extravillous trophoblasts, which were stained for cytokeratin, were stained for HLA-G protein in every woman with an uncomplicated pregnancy. In contrast, clusters of extravillous trophoblasts were insularly devoid of the staining for HLA-G in all the preeclamptic patients. CONCLUSION: The attenuated expression of HLA-G protein on the extravillous trophoblasts could be at play in the pathophysiology of preeclampsia.

Adult↗
PubMed1997

Distribution of type-I interferon-receptors in human first trimester and term placental tissues and on isolated trophoblast cells.

PROBLEM: Type-I interferon (IFN) is the protein recognizing pregnancy in ruminants. Although IFN is secreted in early pregnancy, its role is not still clear in other species. Like other cytokines, IFN exerts its biological functions through specific membrane receptors. We have investigated the potential action of IFN in human pregnancy by studying the distribution of the receptors in the human placenta. METHOD: Reactivity to monoclonal antibodies (mAbs) to the type-I IFN-receptor (R) was analyzed by immunohistochemistry in human placental tissues and in cytospins of first trimester trophoblast cells. RESULTS: Type-I IFN-R immunoreactivity was observed mostly in first trimester villous cytotrophoblasts and in the cytotrophoblast cell columns. Trophoblast in the decidua, the epithelium of the uterine glands, and most of the isolated trophoblast cells were also immunoreactive. CONCLUSION: The expression of type-I IFN-R in the highly proliferating and migrating trophoblast suggests that this cytokine has a role in trophoblast growth and invasion.

Antibodies, Monoclonal↗
PubMed1998

The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome.

PROBLEM: The antiphospholipid (aPL) antibody syndrome is characterized by severe pregnancy complications, the cause of which remains unknown. We hypothesized that the placental trophoblast is a target for aPLs. METHOD OF STUDY: The effects of monoclonal aPLs on trophoblast function, including the invasion of JAR into matrigel-coated filters and the effects of annexin V expression on BeWo, were investigated using choriocarcinoma models. RESULTS: aPLs against phosphatidylserine (PS) significantly (P < 0.001) decreased the migration of JAR across the membrane. In the annexin V studies, undifferentiated BeWo did not express surface annexin V. After differentiation, BeWo expressed surface annexin V, which was removed in the presence of aPLs, resulting in increased binding of prothrombin. CONCLUSIONS: PS is expressed on the trophoblast surface during differentiation and invasion of extracellular matrix. Our data suggest that aPLs against PS can directly affect trophoblast function by limiting the depth of decidual invasion and by concurrently creating a procoagulant surface on trophoblast exposed to the maternal circulation.

Annexin A5↗
PubMed1996

Membrane potential difference and intracellular cation concentrations in human placental trophoblast cells in culture.

1. The electrochemical gradients for Na+ and K+ were assessed in a cell culture model of trophoblast differentiation. 2. Membrane potential difference (Em), intracellular water and Na+ and K+ contents were measured in choriocarcinoma cells (JAr cell line; 96% of which are undifferentiated trophoblast cells) and in mononucleate and multinucleate (differentiated) cytotrophoblast cells isolated from the human placenta at term. 3. There was a significant fall in Em from -57 mV in JAr cells, to -48 and -40 mV in mono-and multinucleate cytotrophoblast cells, respectively. Treatment with ouabain (1 mM for 15 min) depolarized the JAr cell membrane by 15 mV but did not affect cytotrophoblast cell membrane potential. 4. Intracellular K+ concentration was similar in JAr, mono- and multinucleate cytotrophoblast cells but Na+ concentration was higher in mononucleate cytotrophoblast cells compared with JAr cells. 5. Ouabain treatment (3 mM for 15 min) caused a small increase (4.5%) in cell water in mononucleate cytotrophoblast cells but lowered K+ (approximately 30%) and increased Na+ concentration (approximately 125%) in all the trophoblast cells studied. 6. The K+ equilibrium potential (EK) was more negative than Em in all cells and the difference between EK and Em was smaller in JAr cells (-25 mV) than in mono- and multinucleate cytotrophoblast cells (-33 and -43 mV, respectively). 7. The Na+ equilibrium potential (ENa) was positive in the trophoblast cells and the difference between ENa and Em was 122, 100 and 100 mV in JAr, mono- and multinucleate cytotrophoblast cells, respectively. 8. These results suggest that the electrochemical gradient for K+ is affected by the stage of trophoblast cell differentiation. In contrast, the electrochemical gradient for Na+ is similar in mono- and multinucleate cytotrophoblast cells.

Cations↗
PubMed2003

Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface.

Trophoblast adhesion to the uterine wall is the requisite first step of implantation and, subsequently, placentation. At the maternal-fetal interface, we investigated the expression of selectin adhesion systems that enable leukocyte capture from the bloodstream. On the maternal side, human uterine epithelial cells up-regulated selectin oligosaccharide-based ligands during the window of receptivity. On the fetal side, human trophoblasts expressed L-selectin. This ligand-receptor system was functional, because beads coated with the selectin ligand 6-sulfo sLe(x) bound to trophoblasts, and trophoblasts bound to ligand-expressing uterine luminal epithelium in tissue sections. These results suggest that trophoblast L-selectin mediates interactions with the uterus and that this adhesion mechanism may be critical to establishing human pregnancy.

Animals↗
PubMed1998

Promotion of trophoblast stem cell proliferation by FGF4.

The trophoblast cell lineage is essential for the survival of the mammalian embryo in utero. This lineage is specified before implantation into the uterus and is restricted to form the fetal portion of the placenta. A culture of mouse blastocysts or early postimplantation trophoblasts in the presence of fibroblast growth factor 4 (FGF4) permitted the isolation of permanent trophoblast stem cell lines. These cell lines differentiated to other trophoblast subtypes in vitro in the absence of FGF4 and exclusively contributed to the trophoblast lineage in vivo in chimeras.

Animals↗
PubMed1997

Inflammatory cytokine expression is correlated with the level of human immunodeficiency virus (HIV) transcripts in HIV-infected placental trophoblastic cells.

The inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) have been associated with increased human immunodeficiency virus (HIV) expression and enhanced lymphocyte adhesion to trophoblastic cells in experimental systems. To determine if there is a correlation between the expression of these cytokines and the levels of HIV transcripts in trophoblasts of term placentas from HIV-infected women, we studied the placentae of 30 HIV-positive and 13 control gravidae. Twenty-three of the HIV-positive women received zidovudine (ZDV) as prophylaxis against HIV vertical transmission; only one of the seven women who did not receive ZDV was a transmitter, for an overall vertical transmission rate of 3.8%. Cytokine production was measured by enzyme-linked immunosorbent assay in the supernatants of trophoblastic cell cultures. Additionally, cytokine transcripts and HIV gag sequences were determined by a quantitative reverse transcription-PCR assay. In general, trophoblastic cells of HIV-positive placentas expressed significantly higher levels of IL-1beta, IL-6, and TNF-alpha than those of control placentas. All placentas from HIV-positive women expressed HIV gag transcripts at either a low (<156 copies per microg of total RNA) or a high (>156 copies per microg of total RNA) level. There was a statistically significant positive association between the basal level of TNF-alpha production and the level of HIV gag transcripts of HIV-positive placental trophoblastic cells. Nevertheless, these data, coupled with a low transmission rate, would indicate that some other factors, perhaps working in concert with cytokines, are necessary for vertical transmission of HIV from mother to infant.

Cells, Cultured↗
PubMed2001

Cell-to-cell contact results in a selective translocation of maternal human immunodeficiency virus type 1 quasispecies across a trophoblastic barrier by both transcytosis and infection.

Mother-to-child transmission can occur in utero, mainly intrapartum and postpartum in case of breastfeeding. In utero transmission is highly restricted and results in selection of viral variant from the mother to the child. We have developed an in vitro system that mimics the interaction between viruses, infected cells present in maternal blood, and the trophoblast, the first barrier protecting the fetus. Trophoblastic BeWo cells were grown as a tight polarized monolayer in a two-chamber system. Cell-free virions applied to the apical pole neither crossed the barrier nor productively infected BeWo cells. In contrast, apical contact with human immunodeficiency virus (HIV)-infected peripheral blood mononuclear cells (PBMCs) resulted in transcytosis of infectious virus across the trophoblastic monolayer and in productive infection correlating with the fusion of HIV-infected PBMCs with trophoblasts. We showed that viral variants are selected during these two steps and that in one case of in utero transmission, the predominant maternal viral variant characterized after transcytosis was phylogenetically indistinguishable from the predominant child's virus. Hence, the first steps of transmission of HIV-1 in utero appear to involve the interaction between HIV type 1-infected cells and the trophoblastic layer, resulting in the passage of infectious HIV by transcytosis and by fusion/infection, both leading to a selection of virus quasispecies.

Cell Communication↗
PubMed2002

Polarized release of human cytomegalovirus from placental trophoblasts.

Human cytomegalovirus (HCMV) is a ubiquitous infectious pathogen that, when transmitted to the fetus in utero, can result in numerous sequelae, including late-onset sensorineural damage. The villous trophoblast, the cellular barrier between maternal blood and fetal tissue in the human placenta, is infected by HCMV in vivo. Primary trophoblasts cultured on impermeable surfaces can be infected by HCMV, but release of progeny virus is delayed and minimal. It is not known whether these epithelial cells when fully polarized can release HCMV and, if so, if release is from the basal membrane surface toward the fetus. We therefore ask whether, and in which direction, progeny virus release occurs from HCMV-infected trophoblasts cultured on semipermeable (3.0-microm-pore-size) membranes that allow functional polarization. We show that infectious HCMV readily diffuses across cell-free 3.0-microm-pore-size membranes and that apical infection of confluent and multilayered trophoblasts cultured on these membranes reaches cells at the membrane surface. Using two different infection and culture protocols, we found that up to 20% of progeny virus is released but that <1% of released virus is detected in the basal culture chamber. These results suggest that very little, if any, HCMV is released from an infected villous trophoblast into the villous stroma where the virus could ultimately infect the fetus.

Cell Culture Techniques↗
PubMed2005

Impact of the placental cytokine-chemokine balance on regulation of cell-cell contact-induced human immunodeficiency virus type 1 translocation across a trophoblastic barrier in vitro.

Cells constituting the placental barrier secrete soluble factors that may participate in controlling human immunodeficiency virus type 1 (HIV-1) transmission from the mother to the fetus. In this study, we asked whether placental soluble factors (PSF) could limit cell-cell contact inducing HIV-1 production that occurs after inoculation of HIV-1-infected peripheral blood mononuclear cells (HIV-1+ PBMCs) onto trophoblast-derived BeWo cells grown as tight and polarized barriers in a two-chamber system. The activity of recombinant chemokines and cytokines expressed by placental tissue and of factors secreted by either early or term placentae of HIV-1-negative women, was analyzed. We identified chemokines (RANTES and MIP-1beta) and cytokines (tumor necrosis factor alpha and interleukin-8) that decreased and increased, respectively, viral production in trophoblast barrier cells inoculated with HIV-1+ PBMCs. Unexpectedly, factors secreted by either early or term placentae of HIV-1-negative women enhanced viral production. Nevertheless, the same PSF did not favor infection of trophoblastic barriers with cell-free HIV-1 and strongly reduced viral production in PBMCs infected with cell-free HIV-1. Moreover, PSF contained chemokines (RANTES and MIP-1beta) and a cytokine, leukemia inhibitory factor, exhibiting a strong anti-HIV-1 activity in our model of cell-to-cell infection. Together these data suggested that at the maternal interface the global activity of PSF is related to the synergistic action of several soluble factors with a balance in favor of an enhancing activity on the passage of viruses across the trophoblast barrier. This could explain the presence of viral sequences in trophoblasts in all placentae of HIV-1-infected women.

Cell Line, Tumor↗
PubMed2006

Epithelioid trophoblastic tumour: a case report and review of the literature.

Epithelioid trophoblastic tumour (ETT) is an unusual type of trophoblastic tumour, which can cause difficulties in diagnosis and (as a consequence) in treatment. The literature suggests that surgery should be the treatment of choice for ETT as it is not responsive to chemotherapeutic agents, used in the treatment of other types of gestational trophoblastic diseases. This case report describes an ETT, which was initially diagnosed as a carcinoma of the cervix. Surgical management was chosen based on the literature. 6 months later the patient also developed a plasmacytoma and was treated with radiotherapy. The occurrence of ETT and plasmacytoma in combination has never been described before. This case report describes a rare case of an atypical trophoblastic tumour, with problematic differential diagnosis. Treatment of carcinoma of the cervix would have necessitated postoperative radiotherapy, but on diagnosis of ETT, surgical management was considered sufficient. Hence, it is important to consider the occurrence of ETTs, although rare, in patients with atypical cervical or endometrial cancer, and in patients diagnosed with a gestational trophoblastic tumour, who do not respond to appropriate chemotherapy.

Adult↗
PubMed1998

p21WAF1/CIP1 expression in gestational trophoblastic disease: correlation with clinicopathological parameters, and Ki67 and p53 gene expression.

BACKGROUND: The p21WAF1/CIP1 gene mediates growth arrest by inhibiting G1 cyclin dependent kinases and has been considered as a downstream effector of the tumour suppressor gene p53. AIM: To analyse the role of p21WAF1/CIP1 in gestational trophoblastic disease. METHODS: The immunohistochemical expression of p21WAF1/CIP1 gene was measured in 33 placentas, 28 partial hydatidiform moles, 54 complete hydatidiform moles, and 13 choriocarcinomas in paraffin wax embedded tissue. The results were correlated with p53 (DO7) and Ki67 (MIB1) immunoreactivity as well as clinical progress. RESULTS: p21WAF1/CIP1 immunoreactivity was found predominantly in the nuclei of the syncytiotrophoblasts. p21WAF1/CIP1 protein expression correlated with gestational age in normal placentas (p = 0.0001) but not in hydatidiform moles (p = 0.89). Complete hydatidiform moles and choriocarcinomas had a significantly higher p21WAF1/CIP1 expression compared with normal placentas and partial hydatidiform moles (p < 0.001); there was no difference between placentas and partial hydatidiform moles. No correlation between p21WAF1/CIP1 expression and either the proliferation (Ki67) index (p = 0.34) or p53 protein accumulation (p = 0.68) was demonstrated. There was no significant difference (p > 0.05) in p21WAF1/CIP1 expression between the 17 patients who developed persistent gestational trophoblastic disease and those who did not. CONCLUSIONS: This study suggests that p21WAF1/CIP1 expression in trophoblastic disease may be induced by a p53 independent pathway. The proliferative activity of gestational trophoblastic diseases might not be determined solely by the control of the cell cycle operated by p21WAF1/CIP1. p21WAF1/CIP1 expression is not an accurate prognostic indicator of gestational trophoblastic disease.

Biomarkers, Tumor↗