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PubMed1998

Immunohistochemical analysis of cell cycle regulatory gene products in normal trophoblast and placental site trophoblastic tumor.

Intermediate trophoblast (IT) rarely gives rise to a placental site trophoblastic tumor (PSTT) To examine the different growth mechanisms present in normal and neoplastic IT, the expression of cell cycle regulatory molecules was compared at normal implantation sites and in PSTTs. Normal implantation sites in early gestation (19 patients) and PSTTs (6 patients) were immunohistochemically studied using antibodies against cytokeratin, human chorionic gonadotropin, and human placental lactogen to identify IT, and antibodies against Ki-67, cyclins (A, B, D1, and E), cyclin-dependent kinases (cdks), and p53 to investigate the proliferative activity of the trophoblast. Marked proliferative activity was observed in the trophoblast of the cell columns. Normal IT exhibited a very low labeling index for Ki-67, with negative expression for cdks and cyclins, except for cyclins B and E. The tumor cells of PSTT exhibited a high labeling index for Ki-67 with positive expression for all the cyclins and cdks examined. Expression of p53 was identified in tumor cells of PSTTs and the distribution of p53-positive cells correlated topographically with that of the cyclin A-positive cells. The transformed IT of PSTT has high proliferative activity with an abnormal expression of cell cycle regulatory molecules, which is not observed in normal IT.

Adult↗

PubMed1988

[The expression of c-myc, c-fms, c-sis oncogenes in the trophoblast of normal pregnancy and trophoblastic disease].

Recently it has been suggested that proto-oncogene plays a role not only in cellular proliferation, development and differentiation, but also in neoplastic transformation. We now show the expression and its localization of c-myc, c-fms and c-sis proto-oncogenes in human developing chorionic tissue and fresh surgical specimens of mole and choriocarcinoma with the method of Northern blotting and In-situ hybridization. The 2.4kb c-myc transcript has been localized to the cytotrophoblast in early placenta and also localized to the C and S typed trophoblastic cells in mole and choriocarcinoma. The 4.0kb c-fms transcript has been localized to the syncytiotrophoblast, especially the highly differentiated syncytiotrophoblast in the second and third trimesters and S typed trophoblastic cells in mole and choriocarcinoma. Moreover, the 4.0kb c-sis transcript has been localized to the cytotrophoblast in early placenta, but not detected in mole or choriocarcinoma. First, these results suggest that the stage and site specific expression of c-myc, c-fms and c-sis proto-oncogenes are clearly related to the proliferation, development and differentiation of normal trophoblastic cells. Second, the expression of c-myc, c-fms proto-oncogenes may be of particular importance in the tumorigenesis and progression of trophoblastic disease.

Blotting, Northern↗

PubMed2000

Adhesion of trophoblast to uterine epithelium as related to the state of trophoblast differentiation: in vitro studies using cell lines.

At the initial phase of embryo implantation, the trophoblast must have acquired competence for adhesion to the uterine epithelium, a condition whose cell biological basis is far from understood. In the present study, trophoblast-type cells (BeWo, JAr, and Jeg-3 choriocarcinoma cell lines) were treated with retinoic acid, methotrexate, dibutyryl-cAMP, or phorbol-12-myristate-13-acetate in order to modulate their ability to adhere to uterine epithelial cells (RL95-2). In an established model, multicellular spheroids of choriocarcinoma cells were transferred onto the surface of monolayer cultures of RL95-2 cells followed by a centrifugal force-based adhesion assay. In controls, about 45% of BeWo and JAr cell spheroids and 75% of Jeg-3 spheroids adhered to uterine monolayers within 30 min. Pretreatment of spheroids with either of the agents stimulated differentiation as indicated by the rate of chorionic gonadotropin secretion, but consistently reduced the adhesion to the endometrial monolayer in all three choriocarcinoma cell lines. While previous investigations had shown that invasiveness of trophoblast cells (into extracellular matrix) does not seem to be linked to the differentiation program in a simple manner, the present data suggest that such an (inverse) link may indeed exist with respect to the ability to initiate an adhesive interaction with the uterine epithelium. These observations support the view that epithelial cell interactions as typical for the initial phase of embryo implantation are regulated in a way that is clearly different from cell-matrix interactions governing later phases of trophoblast invasion into the endometrial stroma.

Cell Adhesion↗

PubMed2003

Family of Kunitz proteins from trophoblast: expression of the trophoblast Kunitz domain proteins (TKDP) in cattle and sheep.

Here we report the molecular cloning of several members of a family of novel proteins expressed by the ruminant trophoblast, known as the trophoblast Kunitz domain proteins (TKDPs). Each contains a carboxyl-terminal module of approximately 64 amino acids belonging to the Kunitz family of serine proteinase inhibitors. These Kunitz modules are preceded by one or more structurally related domains, each about 80 amino acids long. The function of these domains is unclear. The TKDPs differ considerably in sequence identity, with much of the diversity due to variability in the amino-terminal domains. However, nine of the ten Kunitz domains described here are themselves unique, ranging in amino acid sequence identity from 90% to 53% to each other and averaging only about 50% identity with bovine pancreatic trypsin inhibitor (BPTI). The "warhead" P1 residues, which govern specificity, are themselves variable and include some unusual amino acids, such as Asn, Thr, and Ile, as well as the more common Lys. The Kunitz domains of three of the TKDPs lack the conserved cysteines at positions 14 and 38 (BPTI numbering) that normally contribute to the orientation of the inhibitory loop. Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that the TKDP genes do not exhibit identical expression patterns during trophoblast development, although mostly are expressed maximally during early pregnancy. It is possible that the TKDPs provide a broad range of specificities against maternal proteinases that might be damaging to the trophoblast during pregnancy.

Amino Acid Sequence↗

PubMed1996

Placental-site trophoblastic tumor following metastatic gestational trophoblastic neoplasia.

Placental site trophoblastic tumor generally follows term pregnancy or nonmolar abortion. Thus far, 10 cases of placental site trophoblastic tumor have been described which were preceded by a hydatidiform mole. This is the first reported case where placental site trophoblastic tumor has been preceded by metastatic gestational trophoblastic neoplasia treated by chemotherapy.

Adult↗

PubMed1985

Antibody reactivity against trophoblast and trophoblast products.

Sensitive immunoassays have been applied to WHO reference bank sera from fertile and infertile women in order to assess any naturally occurring antibody reactive with isolated human placental trophoblast membranes or two separate trophoblast protein products (hCG and SP1). A very low incidence of antibody reactive with solubilised trophoblast membrane was detected, and no significant antibody to either hCG or SP1 could be detected. Infertile states represented within this serum bank appear unlikely to involve adverse immune reactions to trophoblast.

Antibodies↗

PubMed1991

Human trophoblast interferon: pattern of response to priming and superinduction of purified term trophoblast and choriocarcinoma cells.

We recently described a beta interferon response of primary cultures of term human trophoblast exposed to poly(I:C). The response pattern has now been studied further with priming and superinduction both of normal placental cell types and JAR, JEG-3 and BeWo choriocarcinoma cells. Pre-treating placental trophoblast cells, fibroblasts and macrophages with human interferon generally led to increased yields of interferon after poly(I:C) induction, whereas choriocarcinoma cells did not respond to priming. All the cells showed the superinduction phenomenon although to varying degrees. The combination of priming and superinduction conditions led to the production of very high yields of interferon in placental fibroblast cultures. The combined procedure also produced more interferon in macrophage cultures than priming or superinduction alone. Combined superinduction and priming of normal trophoblast did not produce higher yields than those obtainable by superinduction alone. These data might help to provide additional insight into the cellular control mechanisms of sensitivity of normal and malignantly transformed cells to interferon. Furthermore, the large quantity of trophoblast interferon produced by superinduction could be used for studies of its anti-viral and immunomodulatory effects.

Cells, Cultured↗

PubMed1990

Placental site trophoblastic tumors (trophoblastic pseudotumors): pathology and clinical importance.

Placental site trophoblastic tumor (PSTT), which can be regarded as a subtype of gestational trophoblastic neoplasia is discussed. The histopathological features include trophoblastic proliferation without the typical organization of the bilamelar cyto and syncytiotrophoblastic villus. Ultrastructural investigation has demonstrated a clone structural relationship between the infiltrating cells and those of the trophoblastic components of the normal human placenta. Clinical management should be based on the complete surgical resection of the mass and a follow-up by measuring the serum levels of beta-human chorionic gonadotropin fractions.

Female↗

PubMed2004

Trophoblast gene expression: transcription factors in the specification of early trophoblast.

Azone of trophoblast specification is established when the embryo is a morula, presumably reflecting a unique combination of transcription factors in that zone of cells and the influence of various environmental cues and growth factors on them. A key first step in this process of specification is the down-regulation of Oct4, a transcription factor that acts as a negative regulator of trophoblast specification and of genes normally up-regulated as the trophectoderm first forms. The transcription factors believed to have a positive association with trophectoderm specification have been inferred primarily in two ways: by their expression patterns in embryos, ES cells and TS cells and by the consequences of gene disruption on embryonic development. Many of these transcription factors also control the expression of genes characteristically expressed in trophoblast but not in the epiblast, primitive endoderm and their derivatives. ES and TS cells from the mouse and other species are beginning to provide insights into the changes in gene expression that accompany lineage specification and the subsequent post-specification events that lead to functional trophoblast derivatives.

Animals↗

PubMed2002

Trophoblast differentiation modulates the activity of caspases in primary cultures of term human trophoblasts.

Cultured human cytotrophoblasts are more susceptible than syncytiotrophoblasts to hypoxia-induced apoptosis. Caspases are cysteine proteases that cleave cellular components to effect the apoptotic cascade. We hypothesized that cultured cytotrophoblasts exhibit a higher activity of caspases when compared with syncytiotrophoblasts. Using western analysis, we demonstrated that the pro-caspases 3, 6, 8, and 9 are expressed in cytotrophoblasts cultured for 24 h, and also, in trophoblasts cultured 72 h when syncytiotrophoblasts have formed. Importantly, we found significantly higher activity of all four caspases in trophoblasts cultured 24 h compared with cells cultured 72 h. Colchicine and DMSO, which hinder trophoblast differentiation, enhanced the activity of all four caspases in cells cultured 72 h. Conversely, caspase activity was reduced in trophoblasts cultured for 24 h in the presence of epidermal growth factor, which enhances differentiation. This effect was most pronounced on caspase 3 and was attenuated by addition of the tyrosine kinase inhibitor AG1478. We conclude that cytotrophoblasts exhibit a higher activity of caspases 3, 6, 8, and 9 when compared with the more differentiated syncytium. This may account for the higher susceptibility of cytotrophoblasts to hypoxia-induced apoptosis.

Amino Acid Chloromethyl Ketones↗

PubMed1991

Trophoblast cell differentiation: establishment, characterization, and modulation of a rat trophoblast cell line expressing members of the placental prolactin family.

The purpose of this investigation was to establish and characterize a cell line derived from a rat choriocarcinoma and to evaluate the usefulness of the cell line as an in vitro model for studying trophoblast cell differentiation. A cell line was generated from choriocarcinoma explants and named Rcho-1. The cell line consisted of a mixture of cell types, including small cells growing in clusters and giant cells possessing very large nuclei. This characteristic morphology was maintained through at least 23 passages and in a series of clonal cell lines isolated from the parent Rcho-1 cell line. The Rcho-1 cell line was capable of expressing placental lactogen-I (PL-I), PL-II, PRL-like protein-A (PLP-A), and PLP-C mRNAs when cultivated in vitro; however, the Rcho-1 cells expressed only PL-I when grown beneath the kidney capsule of host rats. The Rcho-1 cell line did not express PLP-B under any experimental condition. This pattern of placental PRL expression was maintained for 23 passages. Rcho-1 cells synthesized and secreted PL-I, PL-II, and PLP-A proteins with biochemical characteristics similar to those of their placental counterparts. PL-I and PL-II mRNAs were specifically localized to giant cells. Morphological appearance and placental PRL expression were used as indices for monitoring the differentiation state of Rcho-1 cells grown under various conditions. Both morphological and functional trophoblast cell differentiation were induced by maintaining the Rcho-1 cells in postconfluent culture conditions. Postconfluent Rcho-1 cultures were characterized by an increased percentage of giant cells and an induction of placental PRL expression. Some clonal cell lines derived from the parent Rcho-1 cell line exhibited distinct patterns of differentiation and placental PRL expression. In summary, we have established a rat trophoblast cell line capable of expressing a differentiated phenotype. The differentiated phenotype includes both morphological and functional parameters and can be modulated in vitro. This cell line is a unique model for studying the control of placental PRL gene expression and the regulation of trophoblast cell differentiation.

Animals↗

PubMed1982

Specific binding sites for epidermal growth factor and its effect on human chorionic gonadotrophin secretion by cultured tumour cell lines: comparison between trophoblastic and non-trophoblastic cells.

Using human trophoblastic (SCH) and nontrophoblastic (HeLa S3) tumour cell lines, specific binding sites for epidermal growth factor (EGF), a potent stimulator of growth in many tissues, and its effect on secretion of human chorionic gonadotrophin (hCG) and/or its subunits were compared between these two tumour cells. Both SCH and HeLa S3 cells possessed two populations of specific binding sites for 125I-labelled EGF: the high affinity (Kd approximately 10(-10) M) and the low affinity (Kd approximately 7 x 10(-10) M) system. Tetradecanoyl phorbol acetate (TPA), a tumour promotor, showed a potent competitor of labelled tracer binding to its receptor sites in both cell lines. EGF stimulated both hCG-alpha and hCG and/or hCG-beta secretion in a dose-responsive manner from SCH cells, whereas it had no effect on hCG-alpha secretion from HeLa S3 cells. In contrast, dibutyryl cyclic AMP plus theophylline, a phosphodiesterase inhibitor, enhanced hCG-alpha secretion from both cells, while TPA had no effect in either cells. These data suggest that EGF may play a physiological role in hCG secretion from trophoblastic tissues and that the mechanism by which hCG and/or its subunits are secreted may differ between trophoblastic and non-trophoblastic tumour cells.

Bucladesine↗

PubMed2006

Rcho-1 trophoblast stem cells: a model system for studying trophoblast cell differentiation.

The biology of trophoblast cell development can be investigated using in vitro model systems. The Rcho-1 trophoblast stem cell line was derived from a rat choriocarcinoma and is an effective tool for elucidating regulatory mechanisms controlling trophoblast cell differentiation. In this chapter, we describe methods used in the maintenance and manipulation of the Rcho-1 trophoblast cell line.

Animals↗

PubMed2006

Bovine trophoblast cell culture systems: a technique to culture bovine trophoblast cells without feeder cells.

Bovine trophoblastic cells are the first cells to differentiate during embryogenesis and play pivotal role in morphological and physiological development of the placenta. We have developed culture systems for bovine trophoblast stem cells isolated from in vitro fertilized blastocysts in the absence of feeder cells. These cells continuously proliferate in Dulbecco's modified Eagle's/F12 culture medium supplemented with bovine endometrial fibroblast-conditioned medium. The cells possess epithelial morphology, express cytokeratin, and form dome-like structures (vesicles). Methods for the maintenance, subculture, storage, and measurement of bovine trophoblast stem cell growth are described. The cells exhibit characteristics of bovine trophoblastic stem cells and possess the ability to differentiate into binucleate cells and express placental lactogen, prolactin-related protein-1, pregnancy-associated glycoprotein-1, and interferon tau.

Animals↗

PubMed1988

Clinical experience with placental site trophoblastic tumors at the New England Trophoblastic Disease Center.

From 1982-1986, seven patients with pathologically confirmed placental site trophoblastic tumors underwent treatment at the New England Trophoblastic Disease Center. All seven patients presented with nonmetastatic disease; the presenting symptom was vaginal bleeding in six patients and amenorrhea in one patient. Mitotic counts of the tumor may vary among endometrial curettings, hysterectomy specimens, and metastatic lesions. When placental site trophoblastic tumor is diagnosed on endometrial curettage, a thorough metastatic workup should be undertaken. Because of this tumor's poor response to chemotherapy, a diagnosis of nonmetastatic placental site trophoblastic tumor should be followed by prompt hysterectomy.

Adult↗

PubMed1986

[The differentiation antigen of trophoblast expressed on trophoblastic neoplasms (choriocarcinoma and hydatidiform mole) detected by monoclonal antibodies].

To analyse the differentiation and malignant transformation of human trophoblasts, attempts were made to establish monoclonal antibodies (MoAbs) that react with cells at a certain stage of the trophoblast differentiation process. Two MoAbs, TM7-3 and TM3-8, were obtained by immunizing BALB/c mice with a human choriocarcinoma cell line, BeWo. In the cellular radioimmunoassay with 125I-labelled F(ab')2 of goat anti-mouse IgG, they reacted with nine out of ten choriocarcinoma cell lines and five of sixteen non-choriocarcinoma cell lines but not with twenty-six lymphoblastoid cell lines tested. Immunofluorescence and immunoperoxidase stainings showed that these MoAbs reacted predominantly with cytotrophoblast-like, but not syncytiotrophoblast-like components in the tissue of choriocarcinoma or hydatidiform mole, in the normal chorionic villi, cytotrophoblasts were very weakly positive but syncytiotrophoblasts were negative, and in a variety of normal tissues tested, only a part of the urinary tubules of kidney and the ducts of pancreas reacted to these MoAbs. These results suggest that TM7-3 and TM3-8 detect a differentiation antigen of human trophoblasts, which appears to increase with the malignant transformation of cytotrophoblasts. Thus, TM7-3 and TM3-8 may be useful in the study of human trophoblast differentiation.

Antibodies, Monoclonal↗

PubMed1983

[Trophoblastic beta 1-glycoprotein in the blood in trophoblastic tumors].

Trophoblastic beta 1-glycoprotein (TBG) or a "specific protein of pregnancy" isolated from placental extracts and retroplacental serum, is a reliable marker of trophoblastic tumors. A highly sensitive quantitative radioimmunoassay to determine TBG was developed. The use of this method in the Department of Gynecology. All-Union Cancer Research Center, USSR AMS, for a dynamic observation over patients with different trophoblastic tumors for 3 yrs. has shown that TBG is determined in 94.7% of the cases, this antigen concentration correlating with the disease stage and reflecting a clinical course of the disease. Chorionic gonadotropin (CG) determined simultaneously in the urine of the same patients, was found in 84% of the cases. TBG indices correlate with the CG level in 75% of the cases and serve as an important criterion in the diagnosis and evaluation of efficacy of treatment provided to patients with trophoblastic tumors.

Adult↗

PubMed1999

[Trophoblast lesions and trophoblast tumors].

The clinico-pathologic characteristics and the histological/immunohistological differential diagnosis of villous trophoblastic lesions (complete, partial, and invasive hydatiform moles), gestational choriocarcinoma and trophoblastic tumors and pseudotumors of the placental site (placental-site trophoblastic tumor, exaggerated placental site reaction, placental site nodule) are reviewed in context with aspects of cytogenetics, epidemiology and molecular pathogenesis.

Biomarkers, Tumor↗