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PubMed1995

Basal and interferon-induced 2',5'-oligoadenylate synthetase activity in human placental trophoblast and trophoblast-derived malignant cell lines.

Human placental trophoblasts produce interferon (tro-IFNs) when stimulated with viral inducers. Since the antiviral and cellular functions of IFNs are partly mediated by the 2',5'-oligoadenylate synthetase (2-5A synthetase) pathway, the aim of the present study was to determine the basal and IFN-induced levels of 2-5A synthetase in villous trophoblast cultures. A considerable basal level of 2-5A synthetase was observed in syncytiotrophoblast cultures from both first and third trimester. In contrast no basal activity was detectable in placental fibroblast- and trophoblast-derived malignant cell lines (Far, FEG-3, and BeWo). Stimulation with tro-IFN-beta, -alpha and leucocyte-IFN (leu-IFN)-alpha increased the enzyme activity in first and third trimester human syncytiotrophoblast cultures. Treatment with recombinant-IFN (rec-IFN)-gamma significantly enhanced 2-5A synthetase activity in first trimester syncytiotrophoblast, but had no effect on third trimester syncytiotrophoblast. Tro-IFN-beta, -alpha and leu-IFN-alpha induced high levels of 2-5A synthetase activity in placental fibroblast, BeWo and FEG-3 cell-lines, whereas rec-IFN-gamma treatment did not induce 2-5A synthetase activity in any of these cells. No detectable 2-5A synthetase activity was found in the Far cell line. The capability of cells deriving from the fetoplacental unit to raise an antiviral response by the induction of 2-5A synthetase may be important in defending the fetus against viral infection from the mother. Furthermore 2-5A synthetase in cells of the fetoplacental unit may play a role in their normal growth and development.

2',5'-Oligoadenylate Synthetase↗

PubMed2006

Gestational trophoblastic diseases: 3. Human chorionic gonadotropin-free beta-subunit, a reliable marker of placental site trophoblastic tumors.

OBJECTIVES: Placental site trophoblastic tumor (PSTT) commonly presents with low and variable concentration of hCG immunoreactivity in serum which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease (quiescent GTD). Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low hCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. We investigate the usefulness of hCG-free beta-subunit to make this discrimination. METHODS: Data collected on cases referred to the USA hCG Reference Service for consultation served as a basis for this retrospective analysis. There were 13 cases with histology proven PSTT and 12 with nontrophoblastic malignancy. hCG-free beta-subunit was measured by immunoassay and reported as a proportion of total hCG (hCG-free beta-subunit(%)). hCG-free beta-subunit(%) results were determined for all histologically proven cases of PSTT and for the nontrophoblastic malignancies. Comparisons of hCG-free beta-subunit(%) were made and compared with those of the 82 choriocarcinoma/GTN cases and 69 quiescent GTD cases. The accuracy of hCG-free beta-subunit(%) to discriminate these malignancies was analyzed by investigating the areas under receiver-operating characteristics curve +/- standard error. RESULTS: hCG-free beta-subunit(%) was the predominant hCG form in cases of PSTT (mean +/- standard deviation, 60 +/- 19%) and nontrophoblastic malignancies (91 +/- 11%), thus discriminating these diagnoses from choriocarcinoma/GTN (9.3 +/- 9.2%) and from quiescent GTD (5.4 +/- 7.8%). The cutoff of >35% free beta-subunit is proposed. At this cutoff, 100% detection at 0% false-positive is achieved. The accuracy of hCG-free beta-subunit(%) for this discrimination is 100 +/- 0%. At a proposed cutoff of >80%, the free beta-subunit test will also distinguish PSTT from nontrophoblastic malignancy, with 77% detection at 23% false-positive or an accuracy of 92 +/- 3.2%. CONCLUSION: Measurement of the proportion hCG-free beta-subunit(%) was found to be useful in the diagnosis of PSTT using proposed cutoff values of >35% and >80%. While this finding needs to be confirmed by larger studies, it would be reasonable to measure hCG-free beta-subunit(%) whenever the diagnosis of PSTT is considered.

Choriocarcinoma↗

PubMed1996

[The early placental trophoblast. II. Tumorous disorders of trophoblast development].

Many factors can alterate the correct implantation of the blastocyste, e.g. alterations of the tubal micro-environment or inflammatory processes. For correct implantation a mature endometrium is necessary. Other alterations, which can cause an abortion are immunological mechanisms. Gestational trophoblastic disease includes the partial and complete hydatidiform mole, as well as the chorioncarcinoma. Proliferations of the intermediate trophoblast are the placental site nodule or plaque, the exaggerated placental site and the placental site trophoblastic tumor. The distinction of the different causes of malimplantation and abortion are necessary to prevent a further disruption of a following pregnancy.

Cell Transformation, Neoplastic↗

PubMed1993

Progressive expression of trophoblast-specific genes during formation of mouse trophoblast giant cells in vitro.

The expression of a battery of trophoblast-specific mRNAs was studied during trophectoderm development in vivo and in vitro to assess the use of these mRNAs as markers of trophoblast differentiation and to examine lineage relationships between various trophectoderm derivatives. In situ hybridization of sectioned day 6.5-18.5 mouse embryos localized mRNAs for mouse placental lactogens I and II and mouse proliferin (PLF) to trophoblast giant cells and proliferin-related protein mRNA to the spongiotrophoblast and giant cell layers. A fifth marker, cDNA 4311, was found only in spongiotrophoblast. Day 3.5 blastocyst outgrowths and day 7.5 diploid extraembryonic ectoderm (EX) and ectoplacental cone (EPC) were then cultured to produce polyploid giant cells in vitro. Cultures were processed for in situ hybridization after 2, 4, or 6 days. EX and EPC both formed secondary giant cells, which expressed all markers in the same sequence as was observed in vivo, and primary giant cells in blastocyst outgrowths expressed the early giant cell markers PLF and PL-I on days 4 and 6 of culture. EPC progressed through the sequence 2 days ahead of EX, indicating commitment of EPC to giant cell formation. These results suggest that EX, EPC, and primary and secondary giant cells all share in a common pathway of differentiation and that the highly ordered sequence of gene expression characteristic of this pathway occurs similarly in vivo and in vitro.

Animals↗

PubMed1988

Beta lactoglobulin homologue placental protein 14 (PP14) in serum of patients with trophoblastic disease and non-trophoblastic gynecologic malignancy.

Serum levels of beta lactoglobulin homologue placental protein 14 (PP14) were measured by a sensitive radioimmunoassay in various trophoblastic diseases and non-trophoblastic gynecologic malignancies. While trace amounts of protein were detected in sera of non-pregnant subjects (22.3 +/- 13.7 micrograms/l), during first half of normal pregnancy a dramatic rise of serum-PP14 levels was demonstrable with a peak-value at 7th-10th week of gestation, followed by a decline thereafter. Serial determinations of PP14 have been performed in 31 patients with trophoblastic tumour (20 hydatidiform moles, 4 invasive moles and 7 choriocarcinomas). In patients with hydatidiform moles and invasive moles (273.5 +/- 106.5 micrograms/l and 162.2 +/- 109.6 micrograms/l) respective values before therapy were much exceeding the non-pregnant controls. After therapy there was a rapid decline of the serum-PP14 levels within two weeks. In patients with choriocarcinoma the PP14 values were moderately elevated (66.4 +/- 25.7 micrograms/l), and declined following the remission of disease. In 32 gynecological tumours (21 carcinomas of the cervix, 4 endometrial carcinomas, 5 ovarian carcinomas, 2 carcinomas of the vulva) the pretreatment levels were not different to normal controls.

Choriocarcinoma↗

PubMed2003

Expression of the high-mobility group protein HMGI(Y) in human trophoblast: potential role in trophoblast invasion of maternal tissue.

The high-mobility group protein HMGI(Y) is a member of a family of non-histone chromosomal proteins, which have been implicated in the regulation of inducible gene transcription, integration of retroviruses into chromosomes and induction of neoplastic transformation and metastatic progression in cancer cells. The human trophoblast is a tissue that shares proliferation capacity and invasiveness with neoplastic tissues, but in which these processes are tightly regulated. In the present study, we analyzed the expression of HMGI(Y) in the human placenta using immunohistochemistry. We found expression of HMGI(Y), with nuclear localization, in the villous cytotrophoblast (vCT), which is a highly proliferative cell type. In contrast, the majority of the nuclei of the villous syncytiotrophoblast, a terminally differentiated tissue, was negative. Interestingly, expression of HMGI(Y) was strongest in anchoring villi at the implantation site and in extravillous (intermediate) trophoblast (EVT) invading the maternal decidua. As vCT cells differentiate to become EVT, the HMGI(Y) protein appears to switch from a nuclear to a cytoplasmic localization. Expression of HMGI(Y) in isolated trophoblast populations in primary cell culture was also confirmed using Western-blot analysis. This study shows for the first time expression and localization of HMGI(Y) in the subpopulations of placental tissue.

Blotting, Western↗

PubMed1984

Trophoblastic cell sensitivity to 8-day chemotherapy in nonmetastatic gestational trophoblastic neoplasia.

Serial radioimmunoassay determinations of serum beta hCG and methotrexate were compared in two patients with nonmetastatic gestational trophoblastic neoplasia (NMGTN) treated with Goldstein's modification of Bagshawe's intermediate-dose methotrexate-citrovorum factor rescue-treatment program. Pretreatment beta hCG levels (mIU/ml) ranged within the outer limits of the 10(3) log level. Following intravenous methotrexate, sharp serum peaks between 10(-6) and 10(-5) M were observed. Plasma disappearance was rapid with a 3 log drop noted within 24 hr to levels incapable of inhibiting DNA synthesis. beta hCG levels manifested a 1 to 1.5 log drop over the 8 days of chemotherapy and complete remission was noted within 5 to 6 weeks of the first dose of methotrexate. No significant clinical or laboratory toxicity was observed. Although cell culture studies show that 100% of cell death can be achieved with serum levels of 10(-5) M in methotrexate-resistant choriocarcinoma, similar data do not exist for previously untreated trophoblastic neoplastic cells. These preliminary observations suggest that serum methotrexate levels are important for establishing sensitivity levels in a heterogeneous population of trophoblastic cells in NMGTN and that the total dose of methotrexate may be safely preselected on the basis of the pretreatment beta hCG.

Adult↗

PubMed1994

Human trophoblast interferons enhance major histocompatibility complex class I antigen expression on human term trophoblast cells in culture.

The expression and regulation of major histocompatibility complex class I (MHC class I) antigens by virus-induced human trophoblast interferons (tro-IFNs) were examined in term trophoblast cultures. Flow cytometry studies using fluorescence monoclonal antibodies against MHC class I antigens revealed that isolated cytotrophoblasts can express MHC class I antigens. The expression of these antigens increased with stimulation of trophoblast cultures with tro-IFN-alpha and -beta. One hundred IU tro-IFN-alpha and -beta/ml induced no significant higher levels of MHC class I antigens as compared with the control, whereas 1000 IU tro-IFN-alpha and -beta/ml did. The tro-IFN-enhanced expression of MHC class I antigens may be important as it increases the efficiency of local and viral antigen presentation, cytotoxicity by T cell response and local inflammatory processes, thereby preventing virus spread from mother to fetus.

Cells, Cultured↗

PubMed2006

Stellate transformation of invasive trophoblast: a distinct phenotype of trophoblast that is involved in decidual vascular remodelling and controlled invasion during pregnancy.

BACKGROUND: Successful implantation relies on the tightly regulated invasion of extravillous trophoblasts (EVTs). However, little is known about their phenotypic differentiation and relevant motile behaviour. Furthermore, the cell-cell interactions between EVTs and decidual arterioles during physiological transformation are also poorly understood. METHODS: A total of 128 decidual specimens from early and late gestations containing components of EVTs and spiral arterioles were investigated using immunohistochemistry and periodic acid-Schiff reaction. RESULTS: Unipolar, tadpole-like EVTs are observed throughout the interstitial area, with a tendency to decrease along the invasive pathway. The stellate differentiation of the EVTs is identified around and inside decidual arterioles or in the third-trimester myometrium. Furthermore, stellate transformation of EVTs precedes its interactions with the decidual arteriole. These specialized stellate trophoblasts invade and infiltrate the tunica media, accompanying lacuna formation inside the vessel wall and perturbation of actin fibre alignment of the tunica media. CONCLUSION: Stellate transformation of trophoblasts may explain controlled invasion of EVTs and probably plays a key role in initiating cell-cell interaction in decidual vascular remodelling.

Arterioles↗

PubMed1982

Placental site trophoblastic tumour (trophoblastic pseudotumour): a study of four cases requiring hysterectomy including one fatal case.

The clinico-pathological features of four patients with placental-site trophoblastic tumour (trophoblastic pseudotumour) are presented. One patient had the nephrotic syndrome associated with evidence of disseminated intravascular coagulation, with complete resolution after hysterectomy. In two patients the tumour extended beyond the uterus, and one of them died with many metastases in spite of intensive post-operative chemotherapy and 'second look' laparotomy. In three patients the tumour behaved as an actively infiltrative neoplasm resistant to chemotherapeutic regimes usually effective for choriocarcinoma. Serum HCG levels were relatively low compared with those of choriocarcinoma. Histologically the tumours were predominantly composed of mononuclear cells supported by a variable amount of vascular stroma and lacked the bilaminar structure characteristic of choriocarcinoma. Scattered cells stained positively with anti-beta HCG and anti-alpha HCG antisera. Prior curettage was diagnostic in two of three cases. We did not find a clear correlation between mitotic activity and subsequent behaviour. Inflammatory cell infiltration and evidence of organisation around the tumour may be favourable prognostic indicators. We agree with a recent publication stressing the variable behaviour of this tumour, and emphasize the importance of serum HCG monitoring. Total surgical excision is usually feasible and in aggressive cases offers the best chance of eradication. We support the recent suggestion that 'trophoblastic pseudotumour' is an unsuitable name for a potentially lethal disease.

Adult↗

PubMed1995

[Secretion of endothelin-1 by trophoblast cells and binding of endothelin-1 to trophoblast membranes in healthy and pre-eclampsia pregnancies].

OBJECTIVES: The hypothesis was tested that the synthesis or binding of endothelin-1 (ET-1) by the trophoblast are altered in preeclampsia. METHODS: Trophoblast cells (TC) were isolated from 15 normal (C) und 18 pre-eclamptic pregnancies (P). Binding of [125I]ET-1 to plasma membranes of TC was determined after 48 h in culture. Concentration of ET-1 in culture media were measured after each 24 h over 5 day culture period. RESULTS: Specific binding was 150% (week 37-40) - 400% (week 31-36) higher (P < 0.01) in P. In contrast, the release of ET-1 was 60% (week 31-36) - 71% (week 37-40) lower (P < 0.01) in P than in healthy controls. CONCLUSIONS: Pre-eclampsia is associated with a lower release and increased binding of ET-1 by trophoblast cells.

Adult↗

PubMed1977

Development of trophoblast and placenta of the mouse. A reinvestigation with regard to the in vitro culture of mouse trophoblast and placenta.

At 5 days post conceptionem (p.c.) shortly after implantation, giant cell transformation starts at the abembryonic pole of the blastocyst, spreading over the mural trophoblast; 1 day later, the first ectoplacental giant cells appear at the base of the fast growing ectoplacental cone (derived from the polar trophoblast). Giant cell transformation expands over it periphery. Thus, by the 8th day p.c., the conceptus is separated from the maternal tissue by a continuous layer of giant cells, variable in thickness. Giant cells reach their greatest size by 10 days p.c. in the mural tophoblast and by 12 days p.c. in the chorioallantoic placenta. They are probably no longer formed after that stage. Around the 8th day p.c., the allantois reaches contact with the ectoplacental cone, which develops into the chorioallantoic (definitive) placenta. At 9 days p.c., its four zones can already be discriminated: chorionic plate, labyrinth, junctional zone (trophospongium), and zone of giant cells, respectively. Within the next day, the chorioallantoic placental circulation is established. The yolk sac placental circulation is established by the 9th day p.c. The villi of the proximal layer of the yolk sac increase in size and number, and their capillary network becomes more dense until the 12th to 14th day p.c. This provides evidence that the yolk sac placenta exerts its function--to a certain extent--beyond the establishment of the definitive placenta. Around the 14th day p.c., the placental labyrinth reaches its definitive features. Fetal capillaries in the labyrinth, branching from unbilical blood vessels within the septa of connective tissue are surrounded by trophoblast cells. They form a dense vascular network bathing in maternal blood. The structures of the placental zones remain almost the same during further development, the borders becoming sometimes little blurred. Adjacent to the chorionic plate, subchorionic clefts appear at the 14th day p.c. These clefts become confluent to form the intraplacental space, regularly communicating with the yolk sac cavity. At the end of gestation (19th day p.c.) there is a considerable amount of eosinophilic material ('fibrinoid') between the zone of giant cells and the decidua, probably produced by the giant cells.

Animals↗

PubMed1984

Placental site trophoblastic tumour (trophoblastic pseudotumour). A case report.

The term 'gestational trophoblastic disease' includes hydatidiform mole (invasive and non-invasive), choriocarcinoma and a rare condition initially called trophoblastic pseudotumour and more recently placental site trophoblastic tumour. Originally this condition was viewed as benign, but recent reports indicate that it may be fatal. The first report of a South African patient with this uncommon condition is presented.

Female↗

PubMed2000

Workshop Report: Combining the staging system of the International Federation of Gynecology and Obstetrics with the scoring system of the World Heath Organization for Trophoblastic Neoplasia. Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society.

During the past 5 years the International Society for the Study of Trophoblastic Disease and the International Gynecological Cancer Society have moved to modify the staging system for trophoblastic disease by combining the staging of the International Federation of Gynecology and Obstetrics (FIGO) with the scoring system of the World Health Organization (WHO). By making significant changes in both, the classification will be more acceptable worldwide leading to uniform use by physicians reporting management results in trophoblastic disease. This is the report of the Rome Workshop, which will be presented for ratification to the FIGO Staging Committee in September 2000.

Journal Article↗

PubMed1991

Cloning and expression in Saccharomyces cerevisiae of a synthetic gene for the type-I trophoblast interferon ovine trophoblast protein-1: purification and antiviral activity.

Ovine trophoblast protein-1 (oTP-1) is a unique, Type I, trophoblast interferon (IFN) that possesses potent antiviral activity and is thought to be primarily responsible for maternal recognition of pregnancy in sheep. To provide sufficient amounts of protein for detailed studies, a synthetic gene for oTP-1 was designed and assembled in Escherichia coli, subcloned into a yeast expression plasmid, and used to overproduce recombinant oTP-1 in Saccharomyces cerevisiae. Recombinant oTP-1 was purified from soluble yeast extract using sequential ion-exchange and molecular sieve chromatography. Recombinant oTP-1 purified in this fashion exhibited potent antiviral activity (0.6 x 10(8) U/mg) similar to native oTP-1. This expression system will enable production of large quantities of soluble, biologically active, and correctly processed recombinant oTP-1. Furthermore, the synthetic gene construct facilitates introduction of mutations for ongoing structure/function studies of this unique, Type I, trophoblast IFN.

Amino Acid Sequence↗

PubMed1989

Molecular cloning and characterization of complementary deoxyribonucleic acids corresponding to bovine trophoblast protein-1: a comparison with ovine trophoblast protein-1 and bovine interferon-alpha II.

Bovine trophoblast protein-1 (bTP-1) is a secreted glycoprotein that consists of several forms differing slightly in mol wt and isoelectric point. It is produced by bovine conceptuses after about day 15 of pregnancy and is believed to play a key role in signalling the presence of an embryo to the mother. In this study, a series of recombinant cDNA clones corresponding to the mRNA for bTP-1 have been isolated from cDNA libraries representing day 18-19 bovine conceptus poly(A)+ mRNA. Base sequencing of several cDNAs indicated that multiple mRNAs for bTP-1 exist. Northern blotting and primer extension experiments showed that the mRNAs average about 1 kilobase in length. One apparently full-length cDNA clone consisted of 1035 bases up to the beginning of the poly(A) tail. It contained an open reading frame of 195 codons which began at a position 79 bases from the 5' end. Its entire sequence was 85% identical to that of a cDNA for the immunologically related ovine trophoblast protein-1 (oTP-1) and about 79% identical to that for a bovine interferon-alpha II (IFN alpha II). The highest conservation of sequence (greater than 90%) was noted in the 3'-untranslated sequences of the bTP-1 and oTP-1 cDNAs. The deduced amino acid sequence of bTP-1 shared 80% identity with oTP-1, between 45-55% with human, rodent, porcine, and bovine IFNs of the alpha 1 subfamily and about 70% with a bovine IFN alpha II. A single potential site for N-glycosylation was noted at Asn78. These results show that bTP-1, like its ovine counterpart oTP-1, is structurally related to the IFN alpha S. We suggest that these embryonic IFNs play a role in controlling immunoreactions at the trophoblast-uterus interface as well as triggering other maternal responses to pregnancy.

Amino Acid Sequence↗

PubMed1989

Comparative study of placental protein 19, human chorionic gonadotrophin and pregnancy-specific beta 1-glycoprotein as immunohistochemical markers for extravillous trophoblast in pregnancy and trophoblastic disease.

PP19, a new placental tissue protein, has alpha 1-beta 1 electrophoretic mobility, a molecular weight of 36,500 and 3.9% carbohydrate. To study immunocytochemical PP19 localization in extravillous trophoblast, we obtained formalin-fixed specimens from extravillous tubal pregnancy at gestational weeks (GW) 7-9 (12 blocks); four early intrauterine pregnancies at GW 7-13 (12 blocks); four late pregnancies at GW 28-38 complicated with intramural uterine myoma, placenta increta and abruptio placenta (8 blocks); four invasive complete moles (9 blocks); and seven primary and metastatic gestational choriocarcinomas (12 blocks). Immunohistochemical staining was done for PP19, pregnancy-specific beta 1-glycoprotein (SP1) and human chorionic gonadotrophin (hCG) using the indirect-labeled antibody method [purified PP19 (Lot no. 225/242) and antibody against PP19 (Lot no. 632ZA) prepared by H. Bohn, antibodies against hCG (Behringwerke, Marburg, FRG) and SP1 (Dakopatts, Copenhagen, Denmark)]. In both early and late intrauterine pregnancies, the extravillous syncytiotrophoblastic cell (XST) showed positive staining for hCG and SP1 in the cytoplasm, as well as for PP19, which stained more intensively in the nucleus than in the cytoplasm. The three proteins were not seen in the evtravillous cytotrophoblastic cell (XCT) in the trophoblastic cell column and shell. The interstitial cytotrophoblast-like cell (ICT), which infiltrated into the decidua and myometrium, and their blood vessels, was immunoreactively positive for PP19 but negative for hCG and SP1 with the exception of SP1-positive ICT in the myometrium in late pregnancy. XST and ICT in the endosalpinx of tubal pregnancy stained for all three proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗

PubMed1990

Recurrent gestational trophoblastic disease. Experience of the Southeastern Regional Trophoblastic Disease Center.

Between 1968 and 1985, 28 patients with recurrent gestational trophoblastic disease (GTD) were treated at the Southeastern Regional Trophoblastic Disease Center. Sixteen patients received primary therapy at this center and had recurrence diagnosed by re-elevation of human chorionic gonadotropin (hCG) levels after three consecutive negative levels: five (2.5%) of 204 patients with nonmetastatic GTD, three (3.7%) of 81 with good prognosis metastatic disease, and eight (13%) of 61 with poor prognosis disease. The remaining 12 patients were referred for therapy after receiving primary therapy elsewhere. All episodes of recurrence were observed within 36 months of remission with 50% and 85% before 3 and 18 months, respectively. Fourteen (56%) of 25 patients who achieved secondary remission developed a second recurrence and five (45%) of 11 surviving a second recurrence developed one or more further episodes of recurrent GTD. Nineteen patients (68%) have sustained remission 18 months following therapy for recurrent GTD. Factors relating to development and survival of recurrent disease include: poor prognosis metastatic disease, inadequate initial staging and therapy, lack of adequate maintenance chemotherapy beyond the first negative hCG level, and prolonged intervals between cycles of chemotherapy. Recent regimens introduced have contributed to an increasing salvage rate: 15 of 18 patients treated since 1978 are without evidence of disease whereas only four of ten treated prior to 1978 are currently in remission (P = 0.03).

Chorionic Gonadotropin↗