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PubMed1998

[Expression of cell adhesion molecules in the extravillous trophoblast in placentas of preterm pregnancies and in placentas at term].

Invasion of the human trophoblast is regulated by cell adhesion molecules (CAM) such as integrins and members of the immunoglobulin superfamily, which also play an important role in a number of immunological reactions. Abnormal trophoblast invasion of the uterus and its arterial system has been related to preterm delivery. We examined the differences of CAM expression in the extravillous trophoblast of preterm (n = 18) and term pregnancies (n = 21). Placenta and decidua frozen sections were examined by double-staining immunohistochemistry using antibodies against the immunoglobulin superfamily (ICAM-1, ICAM-2, ICAM-3, VCAM-1), integrins (alpha 2 beta 1, alpha 3 beta 1, alpha 4 beta 1, alpha 5 beta 1, alpha 6 beta 1) and cytokeratin. The percentage of immunopositive extravillous trophoblast cells and the intensity of immunoreactivity for the mentioned CAM antibodies was assessed. The expression of alpha 3 beta 1, alpha 5 beta 1 and VCAM-1 (p < 0.05) in the extravillous trophoblast of preterm placentas was lower than in normal placentas, whereas the expression of alpha 6 beta 1 in the extravillous trophoblast of preterm placentas was higher than at term (p < 0.05). No differences were observed for alpha 2 beta 1, alpha 4 beta 1, ICAM-1, ICAM-2 and ICAM-3. Our results show that there is a different expression of cell adhesion molecules in the extravillous trophoblast of placentas in preterm delivery. These differences in CAM might be associated with abnormal immunological and cell-cell interactions between mother and developing fetus and thus cause preterm labor and delivery.

Antibodies, Monoclonal↗
PubMed2003

Pathology of gestational trophoblastic diseases.

Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases. This used to include partial and complete hydatidiform moles, invasive mole, choriocarcinoma and placental site trophoblastic tumour. In recent years, new entities, including epithelioid trophoblastic tumour, have been added to this family. Non-neoplastic and neoplastic lesions derived from implantation site and chorion intermediate trophoblast have been gaining attention in the literature. New markers for trophoblasts have been identified facilitating histological diagnosis in cases with unusual clinical or pathological features. It is worth noting that histological distinction between hydropic abortion and partial mole and between complete and partial moles, especially at early gestational age, may be difficult. It may not be possible to predict progress of the heterogeneous group of GTD from histopathological features, except probably in placental site trophoblastic tumour. Alternative biological markers may be explored for better patient management.

Choriocarcinoma↗
PubMed2004

[Clinicopathological study of intermediate trophoblastic non-tumor lesions: exaggerated placental site and placental site nodule].

OBJECTIVE: To investigate the clinicopathological features of intermediate trophoblastic non-tumor lesions, and to evaluate the position of immunohistochemistry in differential diagnoses. METHODS: Clinical presentation and morphological study of 15 cases of exaggerated placental site (EPS) and 4 cases of placental site nodule or plaque (PSNP) were reviewed. Immunohistochemical stains for hCG, hPL, inhibin-alpha, PLAP, CK18 and Ki-67 were performed. RESULTS: The age of patients ranged from 25 to 40 years with an average of 31.5 years for EPS and 26 to 39 years with an average of 34.3 years for PSNP. Microscopically, EPS was characterized by cords and small sheets of implantation site intermediate trophoblasts infiltrating the endometrium, myometrium and arterial walls. The general histological structures of the endometrium and myometrium were preserved. PSNP was characterized by multiple circumscribed nodular lesions consisting of so-called chorionic-type intermediate trophoblasts and hyaline-like matrix present in the endometrium. Immunohistochemical stainings for hPL and CK18 were positive in the 15 EPS cases. Immunoreactivity for CK18, Inhibin-alpha and PLAP was detected in 4 PSNP cases. The Ki-67 labeling index in 15 EPS cases was low (< or = 5%), while Ki-67 index in 4 PSNP cases was close to 0. CONCLUSIONS: The clinical presentation and pathological features of EPS and PSNP differ from those of trophoblastic tumors (placental site trophoblastic tumor, epithelioid trophoblastic tumor and choriocarcinoma). Immunochemical staining is of great value in their differential diagnoses.

Adult↗
PubMed1991

In vitro development of day-2 equine embryos co-cultured with oviductal explants or trophoblastic vesicles.

This study compared the in vitro development of Day-2 equine embryos co-cultured with either trophoblastic vesicles or oviductal explants. Embryos were collected surgically from the oviducts of pony mares 2 d after ovulation and assessed for stage of development. Culture medium was Ham's F12 and Dulbecco's Modified Eagle's Medium (50:50 v/v) in a humidified atmosphere of 5% CO(2) in air at 38.5 degrees C with either trophoblastic vesicles or oviductal explants. The quality score of embryos was assessed daily. After 4 d in culture, embryos were stained (Hoechst 33342) and evaluated with epifluorescence to determine the number of nuclei present. Six of seven embryos co-cultured with oviductal examples developed to the morula/blastocyst stage, while four of seven embryos co-cultured with trophoblastic vesicles developed to the morula stage. More (P = 0.1) embryos co-cultured with oviductal explants reached the blastocyst stage than embryos co-cultured with trophoblastic vesicles (3/7 vs 0/7, respectively). The number of cells was higher (P = 0.1) for embryos co-cultured with oviductal explants than for embryos co-cultured with trophoblastic vesicles (162.6 +/- 32 vs 87.3 +/- 28, respectively). The number of cells for embryos co-cultured with either oviductal explants or trophoblastic vesicles appeared to be lower than for embryos matured in vivo that were recovered from the uterus at Day 6 (378, 399, >1000). The co-culture of early equine embryos in a completely defined medium with either trophoblastic vesicles or oviductal explants can support development to at least the morula stage. The co-culture of embryos with oviductal explants resulted in superior development of four-to eight-cell embryos, as indicated by the proportion that reached the blastocyst stage and by the number of cells.

Journal Article↗
PubMed2006

Predictors of low risk of persistent trophoblastic disease in molar pregnancies.

OBJECTIVE: To search for predictive factors for low risk of persistent trophoblastic disease in patients with molar pregnancies. METHODS: A total of 270 consecutively collected, histologically confirmed hydatidiform moles were classified by ploidy using karyotyping and flow cytometry. The parental origin of the genome was determined by analysis of microsatellite polymorphisms. Data on clinical features and pathology reports were collected for each patient. RESULTS: The observed frequency of persistent trophoblastic disease in patients with triploid moles was 0 of 105, (95% confidence interval 0-2.8%), whereas 28 of 162 patients with diploid molar pregnancies developed persistent trophoblastic disease (P < .001). Patients with a diploid mole and an initial hCG level lower than 49,000 units per liter did not develop persistent trophoblastic disease (P = .03). CONCLUSION: The risk of persistent trophoblastic disease after a triploid mole is very low. By combining the present data with data from published studies with valid ploidy assessment, the frequency of persistent trophoblastic disease in patients with triploid moles is 0 of 196 (95% confidence interval 0-1.5%). We suggest that the surveillance program for patients with triploid molar pregnancies is shortened. Initial hCG less than 49,000 units per liter is a possible predictor of low risk of persistent trophoblastic disease in women with diploid molar pregnancies, but this observation needs confirmation in larger studies.

Adult↗
PubMed2007

Expression of TGF-beta signaling proteins in normal placenta and gestational trophoblastic disease.

The transforming growth factor beta (TGF-beta) is a vital regulator of placental development and functions. TGF-beta exerts several modulatory effects on trophoblast cells, such as inhibition of proliferation and invasiveness, and stimulation of differentiation by inducing multinucleated cell formation. In this study, we determine the expression patterns of TGF-beta signaling molecules in normal trophoblast, various hydatidiform mole types and choriocarcinoma. A total of 132 cases, including 51 normal placenta (20 first trimester, 11 second trimester, and 20 third trimester) and 81 gestational trophoblastic diseases (17 choriocarcinoma, and 64 hydatidiform moles: 39 complete, 6 partial, and 19 invasive) were immunohistochemically analyzed with anti-TGF beta1/2, TGF-beta receptor type I (TbetaRI), TbetaRII, Smad 2/3, and Smad 4 antibodies on paraffin blocks. In the case of normal placenta, maximal levels of all TGF-beta signaling molecules were observed in villous trophoblast in the first trimester, which decreased with gestational age. Expression of all the TGF-beta signaling proteins except Smad2/3, was significantly enhanced in various moles, relative to normal trophoblast. Moreover, TGF-beta signaling molecules were significantly downregulated in choriocarcinoma, compared to moles. In particular, TbetaRI and Smad2/3 levels were lower in choriocarcinoma than normal villous trophoblast (TbetaRI: p<0.025, Smad2/3: p<0.001). In conclusion, the TGF-beta signaling pathway plays an important role in the pathogenesis and progression of gestational trophoblastic disease, and may thus be employed as a potential therapeutic target and a diagnostic biomarker.

Activin Receptors, Type I↗
PubMed2000

Placental lactogen-I gene activation in differentiating trophoblast cells: extrinsic and intrinsic regulation involving mitogen-activated protein kinase signaling pathways.

Trophoblast giant cells are one of the primary endocrine cell types of the rodent placenta. Placental lactogen-I (PL-I) is the initial prolactin (PRL) family member expressed as trophoblast giant cells differentiate. In this report, we use the Rcho-1 trophoblast cell line as a model for studying the regulation of PL-I gene expression during trophoblast giant cell differentiation. Evidence is provided for trophoblast cell expression of epidermal growth factor receptor (EGFR), ErbB2, fibroblast growth factor receptor 1 (FGFR1), transforming growth factor-alpha, and heparin-binding EGF. EGF and FGF-2 stimulated PL-I mRNA and protein accumulation and PL-I promoter activity in a concentration-dependent manner. These latter growth factor actions on PL-I promoter activities were specifically inhibited by cotransfection with dominant negative constructs for EGFR and FGFRs respectively. Utilization of the mitogen-activated protein kinase (MAPK) pathway by EGF and FGF-2 in trophoblast cells was demonstrated by growth factor stimulation of a Gal4 DNA binding/Elk1 transactivational domain fusion construct, and more specifically by activation of extracellular signal regulated kinase and p38 MAPK. PL-I gene activation was also sensitive to disruption of MAPK and activation protein-1 (AP-1) signaling pathways. In conclusion, autocrine/paracrine pathways involving EGFR and FGFR1, MAPK and AP-1 are shown to participate in the regulation of the PL-I gene in differentiating trophoblast cells.

Analysis of Variance↗
PubMed2003

Gestational trophoblastic disease in the Asian population of Northern England and North Wales.

OBJECTIVE: To determine the incidence and trends of gestational trophoblastic disease in the Asian population of Northern England and North Wales.A prospective observational study. SETTING: Trophoblastic Screening and Treatment Centre, Weston Park Hospital. POPULATION: A total of 3660 women registered with gestational trophoblastic disease between 1991 and 1999. MAIN OUTCOME MEASURES: 1. The incidence of gestational trophoblastic disease in Asian and non-Asian population. 2. Trend in incidence over study period. RESULTS: Three hundred and twenty-two Asian patients were registered. The incidence of gestational trophoblastic disease in the northern part of England and Wales averaged 1 per 714 live births. The incidence of gestational trophoblastic disease in the Asian population was 1.95 times higher than in the non-Asian population (1 per 387 live births vs 1 per 752 live births). There was an excess of molar pregnancies in the extreme maternal age groups; the incidence in these women was twice as high as in the whole reproductive cohort. The ratio of partial to complete hydatidiform mole increased from 0.9 in the lower age to 2.6 in the older age group. There appeared to be a slowly rising trend in the incidence of gestational trophoblastic disease; the increase was higher in the Asian than in the non-Asian population. The ratio of partial to complete moles increased with age in both populations. CONCLUSION: Asian women are at increased risk of having molar pregnancies. Molar pregnancies are more common at the extremes of reproductive age. The setting up of regional or national registration centres has helped to provide more accurate estimates of the true incidence of the disease.

Adolescent↗
PubMed1992

Trophoblast interferons in early pregnancy of domestic ruminants.

A type I interferon (IFN) secreted by the trophoblast of early sheep and cow embryos is thought to be responsible for the maternal recognition of pregnancy. The expression of trophoblast IFN is tissue specific and temporally controlled. However, the isolated bovine trophoblast IFN promoter did not confer tissue specificity on the expression of a bacterial chloramphenicol acetyl transferase (CAT) reporter gene, and could not be induced by virus, unlike other type I IFNs. Trophoblast IFN acts locally within the uterus to prevent luteolysis and prolong progesterone secretion. Endometrial IFN receptors are present, and trophoblast IFN decreases expression of endometrial oxytocin receptor and increases expression of endometrial beta 2-microglobulin, MHC class I antigens and Mx (a mediator of IFN antiviral activity) only in the pregnant horn of pregnant ewes with a transected uterus. The primary effect of trophoblast IFN during early pregnancy appears to be an inhibition of oxytocin receptor expression, although studies in ovariectomized ewes suggest that luteal oxytocin may be required to facilitate the inhibition of prostaglandin F secretion by trophoblast IFN. An investigation of the isolated oxytocin receptor promoter should confirm its critical role in the maternal recognition of pregnancy.

Animals↗
PubMed2001

Expression of TGF-beta signaling genes in the normal, premalignant, and malignant human trophoblast: loss of smad3 in choriocarcinoma cells.

We had earlier shown that TGF-beta controls proliferation, migration, and invasiveness of normal human trophoblast cells, whereas premalignant and malignant trophoblast cells are resistant to TGF-beta. To identify signaling defects responsible for TGF-beta resistance in premalignant and malignant trophoblasts, we have compared the expression of TGF-beta signaling molecules in a normal trophoblast cell line (HTR-8), its premalignant derivative (RSVT2/C), and two choriocarcinoma cell lines (JAR and JEG-3). RT-PCR analysis revealed that all these cell lines expressed the mRNA of TGF-beta1, -beta2, and -beta3, TGF-beta receptors type I, II, and III, and post-receptor signaling genes smad2, smad3, smad4, smad6, and smad7 with the exception that TGF-beta2 and smad3 were undetectable in JAR and JEG-3 cells. Immunoblot analysis confirmed the absence of smad3 protein in choriocarcinoma cells. Treatment with TGF-beta1 induced smad3 phosphorylation and smad3 translocation to the nucleus in the normal and premalignant trophoblast cells. These results suggest that loss of smad3 may account for a functional disruption in the TGF-beta signaling pathway in choriocarcinomas, but not in the premalignant trophoblast.

Choriocarcinoma↗
PubMed2006

Carcinoembryonic antigen and related molecules in normal and transformed trophoblast.

Carcinoembryonic antigen (CEA, CD66e) and CEA-related cell adhesion molecules (CEACAMs) are important mediators in remodeling of diverse human tissues, and modulators of cell proliferation and differentiation. Expression by normal and transformed trophoblast of gestational trophoblastic diseases (GTDs), isolated cytotrophoblast and choriocarcinoma cell lines is presented here. Immunocyto/histochemistry of normal placenta (n=9), invasive mole (n=8), choriocarcinoma (n=7), a placental site trophoblastic tumor, cytotrophoblast in primary culture and JAr and JEG-3 cells was performed using polyclonal anti-CEA and specific monoclonal anti-CEA antibodies. Data were analyzed and scored using Mann-Whitney Test. CEA and CEA-related molecules were identified by Western blot and immunoaffinity chromatography in JAr and JEG-3 cells and extracts of 1st and 3rd trimester of pregnancy tissue and cytotrophoblast cell lysates. CEA is expressed throughout pregnancy, in first trimester predominantly in syncytiotrophoblast, but also in villous cytotrophoblast and extravillous trophoblast. Data presented here demonstrate that CEA is significantly increased in transformed trophoblast of GTDs (p<0.05). Both cytotrophoblast in primary culture and choriocarcinoma cell lines express CEA, with staining of granular deposits in JAr and cell membrane in JEG-3. The results suggest that CEA (CD66e) and other CEA-related protein(s) could be involved in trophoblast differentiation.

Animals↗
PubMed1996

Normal and malignant trophoblasts do not recruit granulated metrial gland cells.

A possible relationship between the development of granulated metrial gland (GMG) cells and trophoblast was studied. Trophoblast implanted in ectopic sites (e.g. kidney capsule) did not induce decidua and did not recruit GMG cells. Only when injected in utero did trophoblast lead to the development of decidua and to the recruitment of GMG cells. With malignant trophoblast (choriocarcinoma cells) similar results were obtained as with normal trophoblast both after ectopic or after in utero injection. The presence of decidua, but not the development of a conceptus or the outgrowth of trophoblast, seems to be required for the differentiation of GMG cells.

Animals↗
PubMed2002

Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells.

Once initiated, invasion of trophoblast cells must be tightly regulated, particularly in early pregnancy. The mechanisms necessary for the invasion and migration of trophoblast cells are thought to be related to those involved in the invasive and metastatic properties of cancer cells. Quantitative PCR was used to measure, in trophoblast cells, the transcriptional expression profiles of four genes, INSL4, BRMS1, KiSS-1 and KiSS-1R, reported to be implicated in tumor invasion and metastasis. Laser capture microdissection and purification of trophoblast cells demonstrate that, as already known for INSL4, BRMS1, KiSS-1 and KiSS-1R are expressed by the trophoblast subset of placental tissues. Expression profiles of these genes studied in early placentas (7-9 weeks, n=55) and term placentas (n=11) showed that expression levels of BRMS1 are higher in term than in early placentas, while expression levels of KiSS-1R are higher in early than in term placentas. Low levels of expression of BRMS1 were observed in normal pregnancies, in molar pregnancies and in choriocarcinoma cell lines BeWo, JAR and JEG3 while, in striking contrast, the expression levels of INSL4, KiSS-1 and Kiss-1R were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. These transcriptional expression profiles are in favor of a predominant role of INSL4, KiSS-1 and KiSS-1R in the control of the invasive and migratory properties of trophoblast cells.

Cell Movement↗
PubMed1992

[Biology of the trophoblastic tissue and placental tumors].

The trophoblast of early placenta has many attributes of malignant tissue: it displays highly proliferative and invasive properties and expresses hormones, growth factors, growth factor receptors and oncogene products. Moreover, this tissue may have an autocrine control of growth. Collectively, these properties are similar to those of malignant tissues and the normal trophoblast is then considered as a "pseudomalignant" tissue. Moreover, either benign (hydatidiform mole) or malignant (choriocarcinoma) trophoblastic disease may be developed from the trophoblastic cells. In this article, the biological features of both the normal and the tumoral trophoblast will be presented. Finally, the trophoblast is a model and a source of molecules of biological interest.

Female↗
PubMed1991

[Effects of various growth factors on the growth of trophoblast cells in long-term culture].

Trophoblasts taken from placental tissue of the 1st trimester and molar tissue, and GCH-1 (gestational choriocarcinoma cell line) cells were cultured in collagen coated dishes. The medium used was a mixture of DME and Ham's F-12 (1:1), containing EGF, PDGF, insulin, GM-CSF, IL-1, -2, -3, PGE1 and PGE2 in various concentrations. 3H-TdR uptake of the cultured cells was measured as a marker of cell growth. The growth of normal trophoblasts was enhanced by PDGF or insulin, and remarkably by EGF + PDGF + insulin + GM-CSF. The growth of molar trophoblasts was accelerated by EGF or insulin. Under these culture conditions, normal trophoblasts have been successfully cultured and maintained for 12 months and molar trophoblasts for 9 months to date. The cultured cells were identified with trophoblasts by immunohistochemical staining with CAM 5.2 monoclonal antibody. No effect of growth factors was observed in GCH-1 cells.

Alprostadil↗
PubMed1967

Ultrastructure of molar trophoblast. Observations on hydatidiform mole and chorioadenoma destruens.

The ultrastructure of molar trophoblast is described in hydatidiform mole and chorioadenoma destruens. Villous molar trophoblast exhibits only minor deviations from normal early villous trophoblast. Invasive trophoblast of chorioadenoma destruens shows features of more-active cell growth, multiplication, differentiation, and degradation. Evidence for evolution of highly differentiated syncytial trophoblast via intermediate stages from primitive undifferentiated cytotrophoblast is confirmed. Cytoplasmic inclusions resembling virus-like particles, observed in chorioadenoma destruens, have not been hitherto described in normal or pathologic trophoblast.

Chorionic Villi↗
PubMedDate not supplied

Regulation of gap junctional communication during human trophoblast differentiation.

During pregnancy, the trophoblast, supporting the main functions of the placenta, develops from the fusion of cytotrophoblastic cells into a syncytiotrophoblast. Gap junction channels consisting of connexins link the cytosols of cells in contact. Gap junctional communication has been involved in the control of cell and tissue differentiation. Recently, a gap junctional communication was demonstrated in trophoblast cell culture by means of the fluorescence recovery after photobleaching (gap-FRAP) technique. This gap junctional communication appeared to be stimulated by human chorionic gonadotropin (hCG). Therefore, the specificity of hCG action and the signalling mechanisms implicated in gap junctional communication were investigated by means of gap-FRAP. In culture, cytotrophoblastic cells develop into cellular aggregates, then into a syncytium, within 1-2 days after plating. During this in vitro differentiation, gap junctional communication was measured, and the maximum percentage of coupling between adjacent cells occurred on the fourth day. In the presence of 500 mIU/ml hCG, the percentage of coupled cells was increased at all stages of culture, and the highest proportion of coupled cells was observed after 2 days instead of 4 days in control conditions. The hCG action was specific, since the addition of heat-inactivated hCG of oFSH or of bTSH did not affect gap junctional communication in trophoblastic cells. The addition of a polyclonal hCG antibody decreased basal gap junctional communication as well as the response to exogenous hCG. Moreover, the presence of 8Br-cAMP (0.5 or 1 mM) mimicked the stimulation by hCG. Interestingly, H89 (2 microM), a specific protein kinase-A inhibitor, dramatically decreased the responses to hCG (500 mIU/ml) and the 8Br-cAMP (0.5 mM) stimulation of trophoblastic gap junctional communication. Calphostin (1 or 2 microM), a specific protein kinase-C inhibitor, strongly stimulated gap junctional communication. In conclusion, the demonstration by means of the gap-FRAP method of a gap junctional communication preceding cellular fusion could be considered as an objective and physiological criterion to mark the beginning of trophoblast differentiation. hCG, a hormone produced by the trophoblast, and two signalling mechanisms are implicated in this phenomenon.

Cell Communication↗
PubMed1996

Connexins and E-cadherin are differentially expressed during trophoblast invasion and placenta differentiation in the rat.

We have characterized the spatial and temporal expression pattern of six different connexin genes and E-cadherin during trophectoderm development in the rat. During the initial phase of trophoblast invasion at 6 days postcoitum (dpc), the trophoblast expressed E-cadherin but no connexin expression could be observed. With progressing invasion of the polar trophoblast into the maternal decidua, from 7 dpc onwards E-cadherin expression in the ectoplacental cone cells was lost and was now restricted to the extraembryonic ectoderm. In the ectoplacental cone and extraembryonic ectoderm instead connexin31 mRNA and protein could be found. This pattern was maintained up to day 10 postcoitum. The start of labyrinthine trophoblast differentiation from day 11 postcoitum onwards was characterized by persisting expression of E-cadherin in the extraembryonic ectoderm and its derivative, the chorionic plate. In addition to E-cadherin, from 10 dpc onwards, connexin26 started to be expressed in the chorionic plate, and both molecules remained coexpressed in the labyrinthine trophoblast of the mature placenta. During this differentiation process connexin31 remained expressed mainly in the proliferating spongiotrophoblast. From day 14 postcoitum onwards, the expression of connexin31 in the spongiotrophoblastic cells decreased, and in parallel they started to express connexin43. The trophoblastic giant cells, first characterized by connexin31, lost all of the investigated connexins during midgestation on day 12 postcoitum but started to express connexin43 from day 18 postcoitum onwards. Our studies suggest that loss of E-cadherin and induction of connexin31 expression is correlated with the proliferative and invasive stages of the ectoplacental cone, whereas appearance of connexin26, E-cadherin and connexin43 reflects the switch to the differentiated phenotypes of the mature placenta.

Animals↗