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PubMed1990

Gestational trophoblastic tumors.

Gestational trophoblastic tumor is a term applied to invasive mole, choriocarcinoma, and placental-site trophoblastic tumor. The overall cure rate in the treatment of these gestational trophoblastic tumors now exceeds 90%. This high success rate is the result of (1) inherent sensitivity of trophoblastic tumors to chemotherapy, (2) ability to monitor therapy effectively with the use of human chorionic gonadotropin as a tumor marker, and (3) identification of prognostic factors which allows categorization of patients into high- and low-risk groups for selection of treatment. Virtually all patients with nonmetastatic and low-risk metastatic disease can be cured using single-agent methotrexate or Actinomycin-D chemotherapy. Intensive therapy with combination chemotherapy including etoposide, high-dose methotrexate and Actinomycin D and, where indicated, adjuvant radiotherapy and surgery has resulted in cure rates of 80-90% in patients with high-risk metastatic disease. The factors which are most important in determining response to treatment are: (1) clinicopathologic diagnosis of choriocarcinoma, (2) metastases to sites other than the lung or vagina, (3) number of metastases, (4) previous failed chemotherapy, and (5) WHO score greater than or equal to 8.

Combined Modality Therapy↗
PubMed2000

Differential regulation of endothelin secretion and endothelin receptor mRNA levels in JAR, JEG-3, and BeWo choriocarcinoma cell lines and in human trophoblasts, their nonmalignant counterpart.

Endothelin (ET) secretion and expression of both ET-A and ET-B receptor subtypes have been found in a number of primary cancers. The present study tested (1) whether choriocarcinoma cells and their nonmalignant counterpart, the trophoblast, secrete ET-1 and express ET-A and ET-B receptors; (2) whether ET-1 secretion and receptor mRNA levels are regulated by the same factors in nonvascular tissues as in vascular tissues; and (3) whether such regulation is similar in malignant and nonmalignant cells. All cells secreted ET-1 in similar amounts (approximately 0.8 fmol/10(6) cells per 24 h) and secretion was unaffected by culture and treatment. Whereas ET-B accounted for almost all (>98%) ET receptor transcripts in the choriocarcinoma cells, the trophoblasts expressed about 20% ET-A receptor mRNA. During control cultures, ET-B mRNA levels rose in choriocarcinoma, with the greatest relative increase (6-fold; P < 0.05 vs 0 h) in BeWo, whereas in trophoblasts, ET-A mRNA transiently changed after 24 and 48 h. Treatment with dexamethasone and glucose did not alter the mRNA levels in all cells. Insulin induced changes (P < 0.05) in ET-B mRNA levels in BeWo (+90 and +60% after 24 and 48 h, respectively) and JEG-3 (-70%), but not in JAR and trophoblast cells. We conclude that malignant transformation affects the responsiveness of the endothelin receptor system to external stimuli and that the regulation of the endothelin system differs in vascular and nonvascular tissues.

Base Sequence↗
PubMed1997

Functional expression on human trophoblasts of interleukin 4 and interleukin 7 receptor complexes with a common gamma chain.

The gamma chain in the high-affinity receptor complex for interleukin 2(IL-2) is used in receptor complexes for IL-4 and IL-7. We examined expression and function of the gamma chain in trophoblast cells. Flow cytometric studies demonstrated that the human placental cell line and choriocarcinoma cell lines expressed the IL-2R gamma chain. None of these cell lines expressed the IL-2R alpha and beta chains, whereas the alpha chains of IL-4R and IL-7R were present. The gamma chain and IL-4R and IL-7R mRNA were detected in human placental trophoblasts by the in situ hybridization method. The release of human chorionic gonadotropin by trophoblasts was accelerated by IL-4 and IL-7 in a concentration-dependent manner. These findings indicate that IL-4 and IL-7 are involved in trophoblast function.

Antigens, CD↗
PubMed1997

Identification of the human leptin 5'-flanking sequences involved in the trophoblast-specific transcription.

Leptin is an adipocyte-derived blood-borne satiety factor that is involved in the regulation of energy homeostasis. We have recently demonstrated nonadipose tissue production of leptin; leptin is synthesized in and secreted from placental trophoblasts (Nature Med. 3: 1029-1033, 1997). To understand the transcriptional regulation of the human leptin gene in placental trophoblasts, we examined the promoter activity of various lengths of the human leptin 5'-flanking sequences in BeWo cells, a human trophoblastic cell line. The 2080-bp human leptin gene promoter region (-2080 to +108) showed a high-level transcription activity in BeWo cells. When DNA sequences between -1885 and -1830 were deleted, the promoter activity was reduced dramatically in BeWo cells. No significant changes in the promoter activity were noted when tested in primary cultures of rat mature adipocytes. Electrophoretic mobility shift assays revealed the presence of nuclear protein(s) binding to the sequences in BeWo cells but not in isolated rat mature adipocytes. The present study provides new insight into the trophoblast-specific transcription of the human leptin gene.

Adipocytes↗
PubMed1993

Spatial and temporal expression of connexin26 and connexin43 in rat endometrium during trophoblast invasion.

The expression of two different gap junction transcripts, connexin26 and connexin43, has been investigated in rat endometrium during implantation and early chorionic-allantoic placentation. An induction of connexin26 protein is detected locally in the epithelium of the implantation chamber prior to trophoblast invasion. At the same stage connexin43 is found exclusively in the primary decidual zone. By the sixth day of pregnancy the uterine epithelium of the implantation chamber has degenerated and the invading trophoblast is directly confronted with the developing decidua. Connexin26 is then detected in decidual cells accompanying the invading trophoblast, whereas connexin43 has spread through the decidual tissue up into the myometrial layers. This distribution pattern of connexin43 and connexin26 is maintained until at least Day 9 of pregnancy. In decidual cells adjacent to the trophoblast both connexins seem to be coexpressed in the same gap junctional plaque. In these early stages of pregnancy a clear correlation exists between levels of connexin43 mRNA and protein expression. In regard to connexin26 mRNA a similar correlation is found from Day 5 of pregnancy onward. The amount of mRNA on Day 4, however, does not correspond to the amount of connexin26 antigen in the endometrium at that stage. The spatial and temporal expression pattern of connexin26 accompanies the process of embryo implantation in the surrounding endometrium, pointing to a specialized function of these cells.

Animals↗
PubMed1995

A novel regulatory region is required for trophoblast-specific transcription in transgenic mice.

The trophectoderm epithelium of the blastocyst is the first tissue to differentiate in the mammalian embryo and gives rise to all cells of the trophoblast lineage. These cells form the majority of the fetal component of the placenta, which is critical for intrauterine development. Our interest in the molecular determinants of trophoblast lineage development has led us to undertake an analysis of the regulatory region of a trophoblast-specific gene termed 4311. The transcription start site was mapped by both primer extension and RNase protection analyses. We show that cloned 4311 upstream sequences are able to confer the correct temporal and spatial expression pattern of 4311 on a reporter gene in transgenic mice. In addition, we have characterized a 340-bp region, 3.7 kb upstream of the transcription start, that is sufficient for the specific expression of lacZ in cells of the developing spongiotrophoblast in transgenic mice. Delineation of a diploid trophoblast-specific regulatory region will facilitate the identification of factors that may regulate the development of this lineage.

Animals↗
PubMed1998

Binding of human IgG and F(ab')2 and Fc fragments to cultured trophoblast cells from human term placenta.

Trophoblast cells, dispersed by trypsin digestion of human term placental villi and purified on Percoll gradient, were maintained in serum-containing medium as monolayer cultures up to 7 days. The initially mononucleated cells, probably cytotrophoblasts, differentiated in culture within 90 h to multinucleated syncytiotrophoblast-like cells. The enigmatic binding of human immunoglobulin G (hIgG) to these cells was studied and compared to the well-known binding of hIgG to cultured human monocytes. Binding of hIgG to cultured trophoblasts at 4 degreesC reached steady state by 0.5-1 h, increased about two- to threefold after 90 h in culture and was linear throughout all concentrations tested (0.00067-132 microM). Fc fragments and even F(ab')2 fragments were found to bind to a similar extent to trophoblasts as the complete hIgG molecules. In contrast, in experiments with cultured monocytes, saturation of hIgG binding could be demonstrated. The binding of complete hIgG molecules and of Fc fragments to monocytes was similar whereas binding of F(ab')2 fragments to monocytes was significantly lower. Our results suggest that, despite morphological and at least partially functional differentiation of trophoblast cells in primary culture, no measurable amounts of functional Fc receptor for monomeric hIgG was expressed.

Binding Sites, Antibody↗
PubMed1998

Differentiation markers and invasiveness: discordant regulation in normal trophoblast and choriocarcinoma cells.

In tumor cells, malignant (invasive) behavior and differentiation tend to be correlated inversely, although it is not clear to what extent this can be generalized and whether it may also apply to normal invasive cell types. We have modulated differentiation of normal trophoblast cells from first trimester or term placenta as well as choriocarcinoma cells (BeWo, Jeg-3, and JAr) with retinoic acid (RA), methotrexate (MTX), dibutyryl-cAMP (dbcAMP), or phorbol-[12-myristoyl-13-acetyl]-diester (PMA). The secretion of the differentiation marker chorionic gonadotrophin was stimulated by nearly all substances in all cell types. The activity of cellular sterylsulfatase showed a tendency to be increased (decreased by RA and dbcAMP in normal trophoblast; not detected in JAr). Invasiveness was decreased by all effectors in normal trophoblast (both types) and in BeWo. In Jeg-3 and JAr, however, PMA treatment (in JAr also RA treatment) increased invasion rates. These results suggest that only in normal trophoblast and in BeWo (but not in other choriocarcinoma cells, i.e., Jeg-3 and JAr) invasiveness and differentiation tend to be correlated inversely. When extrapolating to the various subpopulations of cells within a tumor, induction of differentiation-as intended in certain strategies for tumor therapy ("differentiation therapy")-may have the unwanted effect of stimulating invasiveness in certain subpopulations of tumor cells.

Antigens, Differentiation↗
PubMed1998

Autocrine-paracrine regulation of human trophoblast invasiveness by insulin-like growth factor (IGF)-II and IGF-binding protein (IGFBP)-1.

Trophoblast growth and invasion of the uterus are tightly regulated by locally produced factors. Since insulin-like growth factor (IGF)-II is produced by the invasive human extravillous trophoblast (EVT) cells and IGF-binding protein (IGFBP)-1 by the decidual cells in situ that are in proximity to each other, we examined the possible influence of these molecules on proliferation, migration, and invasiveness of first-trimester EVT cells in culture. These EVT cell functions were respectively measured by 3H-TdR uptake, in vitro migration, and invasion assays. Secretion of invasion-associated enzymes was assessed by zymography, and IGF-binding moieties on the EVT cell were examined by affinity cross-linking. Proliferation of serum-starved EVT cells was stimulated by addition of serum but unaffected by a wide range of IGF-I, IGF-II, and IGFBP-1 concentrations. IGF-II and IGFBP-1 or their combination stimulated EVT cell invasiveness and migration, when assays were conducted in serum-reduced media. Affinity cross-linking studies failed to detect the type 1 IGF receptor, although several IGF-II-specific and IGF-II-preferring binding molecules including type 2 IGF receptor were identified on the EVT cell surface. IGF-II enhancement of invasion was unaffected in the presence of IGF-1 receptor-blocking antibody and IGF-1 failed to influence EVT cell invasion, indicating that type 1 IGF receptor was not responsible for the IGF-II effects. Secretion of gelatinases or plasminogen activators was unaltered by IGF-II or IGFBP-1. We conclude that trophoblast-derived IGF-II and decidua-derived IGFBP-1 provide autocrine/paracrine enhancement of trophoblast invasiveness largely by stimulating migration, an essential step in invasion.

Antibodies↗
PubMed1993

Liver metastases of gestational trophoblastic tumor.

A retrospective study was conducted to determine if a chemotherapy regimen incorporating cis-platinum, etoposide, and actinomycin D (PEA) was associated with an outcome different from that of the standard triple regimen of methotrexate, actinomycin D, and chlorambucil (MAC) in patients with gestational trophoblastic tumor and liver metastases. Subjects were treated at the King Faisal Specialist Hospital Gestational Trophoblastic Center (KFSH-GTC) between January 1980 and December 1990. Of 19 patients with gestational trophoblastic tumor and liver metastases, 6 received MAC chemotherapy, and 8 received PEA. Five patients were terminally ill and received palliative treatment only. Treatment outcome was measured by beta-subunit human chorionic gonadotropin assay (beta-HCG) and by imaging studies which included ultrasound, computerized axial tomography, and/or magnetic resonance imaging. Durable remission was obtained in 5 of 8 (62.5%) PEA-treated patients and none of 6 MAC-treated patients. There was no difference in risk status or World Health Organization (WHO) prognostic score between the two groups. We conclude that PEA is a relatively effective chemotherapy regimen in the treatment of gestational trophoblastic tumor with liver metastases, and it may be worthy of consideration for prospective clinical trials.

Adult↗
PubMed1999

Outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients with persistent gestational trophoblastic tumor.

OBJECTIVE: To determine the outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients treated with chemotherapy for gestational trophoblastic tumor. METHODS: Retrospective record review of patients with gestational trophoblastic tumor who conceived before standard hCG follow-up was completed during 1973-1998. RESULTS: Forty-three patients treated for gestational trophoblastic tumors conceived before human chorionic gonadotropin follow-up was completed. The antecedent pregnancy was complete mole in 31 (72.1%) and partial mole in 12 (27. 9%) patients. Of the 43 patients, 39 (90.7%) had stage I, 1 had stage II, and 3 had stage III disease. The mean interval from human chorionic gonadotropin remission to new pregnancy was 6.3 months (range 1-11 months). Ten patients underwent elective termination and four patients were lost to follow-up. Of the remaining 29 patients, 22 (75.9%) had term live births, 3 (10.3%) had preterm delivery, 3 had spontaneous abortion, and 1 (3.5%) had a repeat mole. Two cases of fetal anomalies were detected; one was inherited polydactyly and the other was hydronephrosis. One patient developed choriocarcinoma with lung involvement and underwent cesarean section at 28 weeks; a normal fetus was delivered and no choriocarcinoma was detected in the placenta. CONCLUSION: Pregnancies occurring in patients treated for gestational trophoblastic tumor before standard human chorionic gonadotropin follow-up is completed may continue under close clinical surveillance since the majority have a favorable outcome. However, patients should also be advised of the low but important risk of delayed diagnosis in case tumor relapse develops during early subsequent pregnancy.

Adult↗
PubMed2002

Cytokeratin 20 as a biomarker of gestational trophoblastic disease: diagnostic and prognostic significance.

OBJECTIVES: This study was designed to examine whether cytokeratin 20 (CK20) is expressed in molar pregnancies and may therefore be used in the diagnosis of gestational trophoblastic disease (GTD). The potential of CK20 expression in predicting the evolution and the prognosis of the different subtypes of GTD was also assessed. METHODS: A total of 48 samples were studied for CK20 expression by RT-PCR methodology. Among these, 24 samples were obtained by curettage of the uterine cavity of patients diagnosed with hydatidiform mole (14 complete moles and 10 partial moles), 4 samples were obtained from choriocarcinoma cell lines (2 JAR and 2 JEG), and 20 samples were of normal trophoblast (control group) obtained from patients that underwent elective termination of pregnancy. RESULTS: Expression of CK20 was identified in all the samples of complete mole (CM), all choriocarcinoma cell lines, and 50% of the patients with partial mole (PM). None of the preparations of normal trophoblastic tissue from the control group expressed the CK20. A significant difference (P < 0.00001) was found in CK20 expression between samples of patients with GTD and control samples. Comparison between CK20 expression in CMs and PMs revealed a significantly more frequent expression of CK20 in CMs (P = 0.006). More than 50% of the patients with PMs that were positive for CK20 had an invasive evolution. CONCLUSIONS: In our opinion, CK20 may assist in distinguishing between molar and normal trophoblastic tissue and may be considered a marker of GTD. In cases in which pathological classification of different subtypes of GTD is in doubt, CK20-positive expression is suggestive for a CM whereas CK20-negative is more indicative for PM.

Biomarkers, Tumor↗
PubMed2000

Genetic insights into trophoblast differentiation and placental morphogenesis.

The placenta is comprised of an inner vascular network covered by an outer epithelium, called trophoblast, all designed to promote the delivery of nutrients to the fetus. Several specialized trophoblast cell subtypes arise during development to promote this function, including cells that invade the uterus to promote maternal blood flow to the implantation site, and other cells that fuse into a syncytium, expand and fold to increase the surface area for efficient transport. Mutation of many genes in mice results in embryonic mortality or fetal growth restriction due to defects in placental development. Several important principles about placental development have emerged from these studies. First, distinct molecular pathways regulate the differentiation of the various trophoblast cell subtypes. Second, trophoblast proliferation, differentiation and morphogenesis are highly regulated by interactions with adjacent cell types. Finally, the specific classes of mutant phenotypes observed in the placenta of knockout mice resemble those seen in humans that are associated with preeclampsia and intrauterine growth restriction.

Animals↗
PubMed2001

Display of complete life cycle of human papillomavirus type 16 in cultured placental trophoblasts.

Human papillomavirus (HPV) infection is threefold more prevalent in spontaneous abortion specimens compared to elective abortions preferentially targeting the placental trophoblasts in these specimens. Here by using infectious ceplar and Southern blot analysis, we demonstrate that the transfected HPV-16 genome de novo replicates in 3A trophoblasts in culture. Peak DNA replication occurred 9-24 days posttransfection, showing classic DNA forms I, II, and III and an 8-kb monomer band upon DpnI/BamHI digestion. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression revealed that E6 and E2 were significantly expressed by day 9, coinciding with HPV-16 DNA replication. However, significant L1 expression was delayed until day 18. L1 protein expression on day 18, but not day 9, was also confirmed by Western blot analysis. The production of HPV-16 virions was demonstrated by three techniques: the appearance of HPV-16 infectious units coinciding with L1 expression, the neutralization of these infectious units with known neutralizing anti-HPV-16 antibodies, and the appearance of spliced E1-E4 and E6-E7 transcripts (RT-PCR) in normal keratinocyte rafts infected with these trophoblast-produced HPV-16 infectious units. These data suggest that HPV-16 is carrying out its complete life cycle in trophoblasts. Previously, HPVs were known to productively replicate only in differentiating keratinocytes of skin. These findings expand HPV biology, support the hypothesis of a possible link between HPV and some spontaneous abortions, and present a new technology for studying HPV.

Cells, Cultured↗
PubMed1992

Under-registration of gestational trophoblastic disease in the Swedish Cancer Registry.

The paper presents a study of completeness of registration of hydatidiform mole and gestational trophoblastic neoplasia in the Swedish Cancer Registry. The study is based on patients treated in Stockholm County, Sweden from 1971 through 1986. Non-notified cases were identified through a computerized register covering nearly all hospital admissions in the region and local hospital patient register. The results show that 25% of the cases with a diagnosis of hydatidiform mole were not included in the cancer register. Of all patients treated for trophoblastic malignancy, 66% were not recorded in the Cancer Registry. The frequent absence of histopathological confirmation in cases with malignant trophoblastic disease was probably the main factor contributing to the observed under-registration. The study indicates that the Swedish Cancer Registry alone does not provide sufficient data for studies on the incidence of gestational trophoblastic disease.

Female↗
PubMed1992

Distribution of laminin, type IV collagen, and fibronectin in the cell columns and trophoblastic shell of early macaque placentas.

The cytotrophoblastic cell columns and trophoblastic shell of macaque placentas accumulate progressively greater amounts of intercellular material during early gestation. We studied the composition of this material in placentas collected from 22-34 days of gestation by using immunoperoxidase techniques directed to the extracellular matrix molecules fibronectin, type IV collagen, and laminin. These antigens co-localized within the intercellular deposits at all stages studied. At day 22 the proximal cell columns were composed of cells with narrow interstices and which lacked immunoreactivity for the 3 antigens. Distally the cells were vacuolated and the intercellular spaces increased in size and contained dense matrix deposits. The trophoblastic shell consisted of closely packed, non-vacuolated cytotrophoblast cells with only a delicate meshwork of matrix. By day 27 the matrix deposits of the distal cell columns increased markedly in size. The trophoblastic shell contained larger numbers of vacuolated cells and was occupied by accumulations of matrix. By 34 days the matrix deposits of the cell columns expanded substantially along the longitudinal axes of the columns. These deposits were often continuous with a matrix-dense, cell-deficient layer in the trophoblastic shell. This matrix-rich zone lay between a cellular layer adjacent to the intervillous space and a similar, but discontinuous, cell layer that formed the junctional zone with the endometrium.

Animals↗
PubMed1989

Malignant and normally developing trophoblastic cells of human placenta display different characteristics defined by histochemical and biochemical mapping of endogenous lectins.

Trophoblastic cells with their strictly controlled propensity for invasive growth hereby bear limited resemblance to malignant cells. Therefore, detailed description of molecular characteristics of this cell type in comparison to histologically related tumor cells may aid in defining physiologically relevant differences. In view of the potential importance of selective protein-carbohydrate interactions in recognitive processes, labelled neoglycoproteins were employed to evaluate systematically the presence and distribution of sugar receptors in tumor cells of chorionepithelioma and in trophoblastic cells of an early stage of gestation. Control reactions in glycohistochemistry, involving prolonged incubation, pH variation and use of nucleotides excluded the possibility that glycosidases or glycosyltransferases govern the sugar-specific binding to the tissue sections. Pronounced differences were detected in the expression of receptors (lectins) for alpha- and beta-glucosides as well as for N-acetylgalactosamine and N-acetylglucosamine. Further differences were revealed by probing both types of tissue with lactosylated, fucosylated, xylosylated and sialylated carrier protein. Upon developmental maturation of the normal cells in placenta the extent of binding of the neoglycoproteins decreased. The glycohistochemical differences between malignant and normally developing trophoblastic cells were found to be reflected in the alteration of expression of certain endogenous lectins, as ascertained by affinity chromatography and gel electrophoretic analysis. Consequently, we assume that the transient presence of certain endogenous lectins during early stages of gestation and their differential expression in relation to tumor cells of chorionepithelioma may be relevant for the special invasive and adhesive behavior of human trophoblastic cells.

Choriocarcinoma↗
PubMed1987

Placental protein 10 (PP10) in the serum of patients with trophoblastic and nontrophoblastic gynaecological tumours.

Serum levels of placental protein 10 (PP10) were measured by radioimmunoassay in patients with trophoblastic (n = 23) and non-trophoblastic (n = 122) gynaecological tumours before, during and after treatment. Elevated levels (greater than 2.0 micrograms/l) were found in 96% of patients with an untreated trophoblastic tumour, and in 22%, 20% and 12% of patients with endometrial, cervical and ovarian carcinoma, respectively. After treatment the levels fell in patients with trophoblastic disease. Although PP10 may be tumour-associated in such cases, it is premature to assume any significance for PP10 as a tumour marker in clinical practice, because changes in serum hCG levels are much more informative.

Female↗