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PubMed2003

Pre-eclampsia and maternal anaemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast.

During pregnancy extravillous trophoblast invades maternal uterine tissues and remodels spiral arteries. Maternal anaemia and early onset pre-eclampsia are associated with perturbed trophoblast biology. We systematically compared numerical density, invasive depth and apoptosis rates of extravillous trophoblast in uterine tissues taken from hysterectomies following Caesarean section after normal pregnancies (n=4) or pregnancies complicated by pre-eclampsia (n=5) or anaemia (n=6). Full thickness sections of the placental bed were studied by immunohistochemistry using anti-active caspase 3, anti-cytokeratin 7, anti-lamin B, M30, Mib-1, anti-PARP, and by the TUNEL assay. In normal pregnancy extravillous trophoblast invaded 2.04+/-0.19 mm (mean+/-SEM ) from the endometrial-myometrial border into the myometrium; in pre-eclampsia 0.67+/-0.14 mm (P< 0.01), and in anaemia 3.84+/-0.21 mm (P< 0.001). The endometrial trophoblast density in normal pregnancy was 2.44+/-0.37 cells per 60,000 microm(3), in pre-eclampsia was 1.04+/-0.15 (P< 0.01), and in anaemia was 3.10+/-0.32. The rate of apoptotic extravillous trophoblast (M30-positive) in the endometrium in normal pregnancy was 7.17+/-1.46 per cent, in pre-eclampsia 4.4+/-0.71, and in anaemia 2.1+/-0.42 (P< 0.01). Maternal anaemia leads to general tissue hypoxia throughout gestation. Increased invasive depth could be explained by hypoxia-stimulated mitosis and decreased apoptosis of extravillous trophoblast. Reduced trophoblast invasion in pre-eclampsia cannot be explained by higher rates of apoptosis.

Adult↗
PubMed2000

[Human amniotic fluid transferrin stimulates progesterone production by human trophoblast cells in vitro].

OBJECTIVE: During pregnancy transferrin plays a key role as an iron transport protein to serve the increased fetal demands of iron. Transferrin is also present in relatively high concentrations in amniotic fluid [6], showing a different glycosylation compared with serum transferrin. The biological function of human amniotic fluid transferrin (hAFT) is still unknown. In addition trophoblast cells also synthesise transferrin. Transferrin synthesised by the trophoblast shows a special glycosylation. We found identical carbohydrate structure of hAFT and trophoblast transferrin. We investigated the influence of hAFT on the progesterone-, cortisol- and hCG-release of trophoblasts in culture compared with the influence of human holo- and apo-serum transferrin on the release of these hormones. MATERIAL AND METHODS: Cytotrophoblast cells were prepared from human term placentae by standard trypsin-DNAse dispersion of villous tissue followed by a percoll gradient centrifugation step. When placed in culture, the trophoblasts were incubated with varying concentrations (50-300 micrograms/ml) of human amniotic fluid- and serum-transferrin. Unstimulated cells of each placenta used as controls. Culture supernatants were assayed for progesterone, hCG and cortisol by enzyme-immunometric methods. RESULTS: Our results show, that the release of progesterone increased in hAFT-treated cell cultures compared to untreated cell cultures. Holo- and apo-serumtransferrin did not show any effect on the progesterone release by trophoblast cells in vitro. Neither hAFT nor holo- and apo-serum transferrin had any effect on the cortisol- and hCG-release in vitro. CONCLUSIONS: Progesterone is a marker for differentiation of trophoblasts in syncytiotrophoblasts. Only hAFT stimulates the progesterone production. We suggest, that hAFT can modulate the endocrine function of trophoblast cells in culture by regulating progesterone production.

Amniotic Fluid↗
PubMed2001

Expressions of proliferation markers (Ki-67, proliferating cell nuclear antigen, and silver-staining nucleolar organizer regions) and of p53 tumor protein in gestational trophoblastic disease.

OBJECTIVE: This study was undertaken to determine whether the expressions of 3 proliferation markers (Ki-67, proliferating cell nuclear antigen, and silver-staining nucleolar organizer regions) and of p53 tumor protein could differentiate spontaneous abortions from gestational trophoblastic diseases and also discriminate among gestational trophoblastic disease subgroups. STUDY DESIGN: Twenty-two partial hydatidiform moles, 17 complete hydatidiform moles, 6 invasive hydatidiform moles, and 20 nonhydropic spontaneous abortions (control group) were evaluated by means of immunohistochemical techniques with antibodies to Ki-67, proliferating cell nuclear antigen, and p53. One-step silver staining was used to detect silver-staining nucleolar organizer regions. RESULTS: The expressions of Ki-67, proliferating cell nuclear antigen, silver-staining nucleolar organizer regions, and p53 were significantly higher in the gestational trophoblastic disease group than in the control group. The results of linear discriminant analysis showed that silver-staining nucleolar organizer region count had the highest sensitivity and specificity (93.3% and 100%, respectively) for distinguishing gestational trophoblastic disease from spontaneous abortion. Sensitivity and specificity for discriminating gestational trophoblastic disease from spontaneous abortion increased to 100% when all four markers were used together. Proliferating cell nuclear antigen was found to be the best discriminating variable for differentiating among gestational trophoblastic disease subgroups. CONCLUSION: Our findings suggest that expressions of Ki-67, proliferating cell nuclear antigen, silver-staining nucleolar organizer regions, and p53 may aid in the diagnosis of gestational trophoblastic diseases. These fairly rapid, simple, and economic techniques could serve as a useful adjunct to conventional methods in the diagnosis of gestational trophoblastic diseases.

Abortion, Spontaneous↗
PubMed2002

Extracellular pH modulates the secretion of fibronectin isoforms by human trophoblast.

Differentiation of human trophoblast from the proliferative to the invasive phenotype takes place in a hypoxic and thus likely an acidic microenvironment. During differentiation, the secretion pattern of fibronectin isoforms changes. Therefore, we analysed the relation between extracellular pH, secretion of fibronectin splice variants and invasiveness. By means of immunohistochemistry and biochemistry, cellular non-oncofetal fibronectins were found in placental stroma and around extravillous trophoblast, whereas oncofetal isoforms only marked the extracellular matrix of extravillous trophoblast. In vitro, mesenchymal cells produced non-oncofetal fibronectins only, whereas choriocarcinoma cell lines, extravillous trophoblast and choriocarcinoma/trophoblast hybrid cells secreted both non-oncofetal and oncofetal isoforms. When the pH of the culture medium was either lowered or increased (between 6.0 and 8.0), the trophoblast hybrids, but not choriocarcinoma and mesenchymal cells, responded with increased secretion of fibronectins and a shift towards oncofetal isoforms. These changes were preserved after pH normalisation. Histochemical determination of local tissue acidity revealed that the site of the lowest detectable tissue pK coincided with the starting point of invasion, the proximal part of trophoblastic cell columns. Therefore, it is concluded that the local pH plays an important role as regulator of differentiation of human trophoblast as reflected by the synthesis of oncofetal fibronectins by the invasive phenotype of extravillous trophoblast.

Blotting, Western↗
PubMed1991

Cell-mediated infection of human placental trophoblast with HIV in vitro.

In order to investigate how human immunodeficiency virus (HIV) gains entry to the placenta, we have performed in vitro experiments in which highly purified trophoblast cells isolated from term human placentas were examined for their susceptibility to HIV infection. Trophoblast cells were exposed to cell-free HIV-1 for up to 24 h, after which the cultures were monitored by p24 antigen capture assay, reverse transcriptase assay, and electron microscopy for evidence of virus uptake and replication. None was found. In the second series of experiments, trophoblast cells were cocultured with HIV-infected MOLT-4 cells for 24 h, stained using an anti-HIV antibody, and examined by immunofluorescence microscopy. The MOLT cells were strongly positive, as expected, but many trophoblast colonies also showed a punctate staining pattern. Examination of similar cultures using the electron microscope revealed MOLT cells adherent to trophoblast but no evidence of cell-cell fusion. Virions were observed in coated pits at the trophoblast cell surface and in endosomes or multivesicular bodies in the cytoplasm. These observations are consistent with an endocytosis-mediated mechanism of virus entry. Virions were also observed budding from the trophoblast plasma membrane, indicating that these cells can support HIV replication. To our knowledge, these results show for the first time that HIV can infect placental trophoblast cells in vitro. The results suggest that the placenta could become infected with HIV by the interaction of virus-infected maternal lymphocytes with syncytiotrophoblast bordering the maternal blood in the intervillous space.

Female↗
PubMed2005

Transforming growth factor-beta induces differentiation of the labyrinthine trophoblast stem cell line SM10.

The mammalian placenta consists of different trophoblast cell types that assist in the variety of functions required for the maintenance of pregnancy. In rodents, labyrinthine trophoblasts of the placenta are especially important, because they are capable of differentiating into fused labyrinthine cells, which form the feto-maternal exchange surface. Even though the molecular signals triggering labyrinthine trophoblast differentiation are poorly understood, transforming growth factor-beta (TGF-beta) has been shown to be present in the placental environment and alter trophoblast development. In this study, we investigated the effects of TGF-beta on the differentiation of the labyrinthine trophoblast stem cell lines SM10 and HRP-1. RT-PCR analyses demonstrated that while the molecular expression of labyrinthine-specific lineage markers (Esx1, Tfeb, and Tec) was maintained in TGF-beta-treated SM10 and HRP-1 cells, TGF-beta induced the down-regulation of trophoblast stem cell markers Id2 and Cdx2. In contrast, TGF-beta induced the expression of a marker of differentiated labyrinthine trophoblasts, Gcm1, only in the SM10 cell line. Furthermore, we demonstrated an increased glucose uptake in the TGF-beta-treated SM10 cells, indicative of functional differentiation. Finally, cell fusion in TGF-beta-treated SM10 and HRP-1 cells was investigated by western blotting analysis of placental alkaline phosphatase and cadherin-11 and by microscopic analyses of cell morphology using green fluorescent protein (GFP) and rhodamine phalloidin staining. The western blotting and morphological analyses indicate TGF-beta-induced cell fusion and morphological differentiation in the SM10 cell line. The SM10 cell line will provide a new and unique model for detailed analysis of TGF-beta-induced molecular events associated with labyrinthine trophoblast differentiation and function.

Animals↗
PubMed1998

The phagocytic activity of human first trimester extravillous trophoblast.

It has been suggested previously that phagocytic activity in the human placenta is confined to cells of the macrophage lineage. However, earlier studies were hampered by the paucity and poor viability of cells inherent in primary trophoblast cell cultures, contamination by other cell types which themselves have phagocytic activity, lack of reliable markers of trophoblasts, and by limitations of methods available to demonstrate unequivocally the internalization of particulate material. We have overcome these limitations by using: (i) DNA transfection to provide unlimited supplies of pure trophoblast cell lines; (ii) human placental lactogen as a marker unique to trophoblast; and (iii) confocal microscopy to demonstrate unequivocally the intracellular locality of phagocytosed material. We found that both untransfected primary culture extravillous trophoblast cells, as well as the cell lines, had the capacity to phagocytose sheep red blood cells, Staphylococcus aureus and baker's yeast cells, and that this activity was inhibited by cytochalasin B and by culture at 4 degrees C. Phagocytic activity in trophoblast cells was less avid than that seen in a professional phagocyte. In physiological and pathological situations where tissue remodelling occurs, such as the rapid turnover in the periodontal ligament or during inflammation, epithelial cells and other cells that are not considered professional phagocytes actively phagocytose components of the extracellular matrix. We postulate that phagocytosis by human trophoblasts may play an important role in the extensive tissue remodelling that occurs during trophoblastic invasion of the decidua.

Animals↗
PubMed1999

Role of the IGF system in trophoblast invasion and pre-eclampsia.

Insulin-like growth factor-II (IGF-II) and IGF binding protein-1 (IGFBP-1) appear to play an important role in paracrine interactions at the maternal-fetal interface in human pregnancy. Patterns of expression of IGF-II and IGFBP-1 at the decidual-trophoblast interface suggest paracrine interactions occur between the IGF-II-expressing invading cytotrophoblast and maternal decidua-derived IGFBP-1. Autocrine/paracrine actions of trophoblast-derived IGF-II may be important in invasion, and for both trophoblast and decidual function. The actions of IGFBP-1 in binding IGF, and as an integrin ligand, suggest it may have multiple roles in the interactions between the invading trophoblast and the maternal decidua. Abundant decidual IGFBP-1 may interact with the IGF-II-expressing, protease-secreting trophoblast to modulate invasion. In-vitro studies of trophoblast-decidual cell interactions in invasion, and clinical observations in a gestational disorder with shallow placental invasion such as pre-eclampsia, have provided new insights into the possible role(s) of IGFBP-1 in trophoblast invasion. The precise mechanisms underlying IGF and IGFBP-1 action at the decidual-trophoblast interface remain to be elucidated. The potential predictive value of serum IGFBP-1 concentrations in pre-eclampsia also remains to be established.

Decidua↗
PubMed1998

Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester.

Tumour suppressor genes may have a role in the control of trophoblast cell population expansion as trophoblast invasion occurs. To investigate this hypothesis, the location of tumour suppressor gene and proto-oncogene products were studied at various stages of trophoblast differentiation and invasion. Trophoblast and decidua were obtained from eight women having a therapeutic termination of pregnancy. Immunohistochemistry was used to localize the products of c-myc, c-erB-2, RB, BCL-2, P21, and P53 genes and anti-cytokeratin was used to identify fetal cells amongst the maternal decidual cells. The most differentiated and furthest invading trophoblast cell type, the multinucleated trophoblast, expressed a combination of genes which may indicate a high apoptotic rate. The other fully differentiated trophoblast, the syncytiotrophoblast, expressed BCL-2 suggesting protection from apoptosis. The co-occurrence of proto-oncogenes and the products of tumour suppressor genes in first trimester trophoblast suggests an important role not only in negative regulation of cellular invasion but also in population expansion through the presence of oncogenes and anti-apoptotic proteins.

Apoptosis↗
PubMed1993

Expression of integrins by human trophoblast and differential adhesion to laminin or fibronectin.

The process of placental implantation involves a series of transformations of trophoblast from a single polarized epithelial layer resting on a basement membrane (villous trophoblast), to cellular aggregates (trophoblast columns) which ultimately disperse to invade uterine decidua as individual cells (interstitial trophoblast). Such tissue re-modelling is associated with changes in the constituents of the extracellular matrix and in the expression of matrix receptors by the cells, the most relevant being the family of integrins which bind to laminin and fibronectin. In this study we show, by immunohistology and flow cytometry, a gradual loss of laminin receptors with the concomitant acquisition of fibronectin receptors as trophoblast is transformed from the villous phenotype, through the cell columns, into the extravillous population. The pattern of staining for the alpha 5, alpha 6, beta 1 and beta 4 subunits indicates that the integrins expressed by trophoblast are predominantly the alpha 5 beta 1 and the alpha 6 beta 4 heterodimers. We have also shown that isolated trophoblast cells assume a flattened, sessile phenotype when cultured on laminin but exhibit a more spreading, motile morphology when plated on fibronectin. In addition, numerous multinucleated giant cells are observed on a fibronectin substrate. Our data suggest that the relative expression of laminin and fibronectin receptors may determine the morphology and behaviour of trophoblast during the process of implantation.

Cell Adhesion↗
PubMed2003

Requirement of gap junctional intercellular communication for human villous trophoblast differentiation.

During pregnancy, the villous trophoblast develops from the fusion of cytotrophoblastic cells (CT) into a syncytiotrophoblast (ST), supporting the main physiological functions of the human placenta. Connexin43 (Cx43) is demonstrated in situ and in vitro in the villous trophoblast between CT and between CT and ST. Moreover, the presence of a gap junctional intercellular communication (GJIC) during in vitro trophoblast differentiation was previously demonstrated. Because the exchange of molecules through gap junctions is considered to play a major role in the control of cell and tissue differentiation, we studied the effects of a gap junctional uncoupler, heptanol, on morphological and functional trophoblast differentiation and on GJIC measured by the fluorescence recovery after photobleaching method. We found that when the GJIC was interrupted, CT still aggregated but fused poorly. This morphological effect was associated with a significant decrease of trophoblastic-specific gene expression (beta human chorionic gonadotropin and human chorionic somatomammotropin). This blocking action was reversible as demonstrated by recovery of GJIC and trophoblast differentiation process after heptanol removal. Moreover, the inhibition of the trophoblast differentiation did not affect Cx43 transcript expression and Cx43 protein expression. These data suggest that the molecular exchanges through gap junctions preceding cellular fusion are essential for trophoblast differentiation generating the multifunctional syncytiotrophoblast.

Cell Communication↗
PubMed1994

Lysis of porcine trophoblast cells by endometrial natural killer-like effector cells in vitro does not require interleukin-2.

Cells with cytotoxic activity against the cell line K562 and expressing perforin have been demonstrated in endometrial cells isolated from pigs early in pregnancy. This study was designed to determine whether porcine trophoblast cells were susceptible to these endometrial effector cells in vitro. Pregnant gilts (n = 8) were slaughtered between Days 17 and 20 of gestation. Immediately after slaughter, both the endometrial effector cells and trophoblast cells were isolated enzymatically from each animal. Enzymatically dispersed endometrial cells were further fractionated by size at unit gravity, whereas trophoblast cells were enriched by discontinuous density centrifugation on Percoll. Cytolytic activity was evaluated against Na2 51CrO4-labeled trophoblast and K562 cells. Comparison was made between freshly prepared and interleukin-2 (IL-2)-stimulated effector cells. The effect of prostaglandin E2 (PGE2) was tested by including it directly in the 51Cr-release assay. The results indicated that porcine trophoblast cells, like K562 cells, could be recognized and directly lysed by endometrial effector cells. Preculture of effector cells with IL-2 was not required for target lysis but enhanced their cytolytic activity against both trophoblast and K562 targets. In contrast, PGE2 exhibited highly suppressive effects on the cytotoxic activity of both freshly isolated and IL-2-stimulated endometrial effector cells. Conjugate assays demonstrated the binding of trophoblast and K562 targets by effector cells of similar morphology. Cold-target inhibition assays suggested that the effectors in porcine endometrial cell preparations that killed trophoblast and K562 cells were the same NK cell-like population.

Animals↗
PubMed1995

Horse trophoblasts produce tumor necrosis factor alpha but not interleukin 2, interleukin 4, or interferon gamma.

The distribution of four cytokines was analyzed in the endometrium and trophoblast of the horse between Days 30 and 55 of gestation. Endometrial tissues, invasive trophoblast (chorionic girdle), and noninvasive trophoblast (chorion and allantochorion) were examined separately. Cytokine expression was determined by amplification of specific mRNA via the reverse transcriptase polymerase chain reaction (RT-PCR). Messenger RNA for interleukin 2 (IL-2), interleukin 4 (IL-4), and interferon gamma (IFN gamma) was detected in endometrial tissues, unstimulated peripheral blood lymphocytes, and control kidney tissue, but not in trophoblasts. leukocytes resident in the endometrium or traversing the uterus via blood vessels might be the source of these cytokines. Endometrial tissues and invasive and noninvasive trophoblasts expressed mRNA for tumor necrosis factor alpha TNF alpha). Immuonoreactive TNF alpha protein was detected in different cell types of the endometrium and in the invasive and noninvasive trophoblast. The ubiquitous expression of TNF alpha by the endometrium and trophoblasts suggests that this cytokine might have an important role in regulating placental growth and differentiation or maternal leukocyte responses to trophoblasts. IL-2, IL-4, and IFN gamma might have important immunoregulatory roles within the endometrium.

Animals↗
PubMed1987

Trophoblast does not cause the cytotoxic T lymphocyte generation due to the lack of ability to stimulate interleukin-2 production.

Trophoblast was demonstrated to be unable to cause the production of interleukin-2 (IL-2) by allogeneic splenocytes in vitro in two ways: 1) The addition of lymphocyte-trophoblast culture-supernatant (LTC-SN) did not stimulate the proliferation of IL-2 dependent cytotoxic T lymphocyte (CTL-L cells; 2) When responder cells were cultured with heat-treated splenocytes (usually no CTL generation) an increase of CTL formation could be seen in the presence of mixed lymphocyte culture-supernatant (MLC-SN) but not of SN from the cultures in which trophoblast cells served as stimulators. In parallel, the trophoblast cells were found to be very poor stimulators of alloreactive CTL. The addition of interleukin-2-enriched media resulted in a significant amplification of trophoblast-induced CTL generation. The resulting killing lymphocytes were capable of destroying the only specific targets, did not lyse syngeneic target cells, and could not be generated in the absence of allogeneic trophoblast. The incubation of these lymphocytes with anti-Thy 1.2 monoclonal antibody in the presence of complement eliminated their killing effect. Lack of class II antigenic determinants on the surface of trophoblast and/or local immunosuppression of IL-2 production by trophoblast cells seem to be responsible for nondelivery of helper factor, which is essential for CTL production.

Animals↗
PubMed1996

Comparison of immunosuppressive properties of hydatidiform mole decidua and trophoblast extracts.

PROBLEMS: The immunologic privilege afforded the fetus relies upon immunoregulation within the maternal-fetal interface. Trophoblast and decidua-derived immunoregulatory factors enforce this privilege by locally suppressing maternal responses to trophoblast antigens. The relative contribution of trophoblast or decidua immunosuppressive factors to pregnancy immunotolerance are not well characterized. The purpose of this study was to compare the suppressive effects of hydatidiform mole trophoblast and decidua extracts on interleukin-2-dependent proliferation. METHOD: Tissue extracts were prepared from hydatidiform mole trophoblast and decidua following uterine evacuation. Samples were submitted to interleukin-2-dependent and -independent cell proliferation assays. RESULTS: Hydatidiform mole trophoblast extract significantly (P < 0.05) suppressed interleukin-2-dependent proliferation but did not affect interleukin-2-dependent cell proliferation. In contrast, molar decidua extract suppressed both cell lines. CONCLUSIONS: Human hydatidiform mole trophoblast contains factor(s) that specifically abrogate interleukin-2-dependent clonal expansion of murine cytotoxic T-cells. In contrast, extracts of molar decidua suppressed both interleukin-2-dependent and -independent responses. This indicates that the trophoblast antagonizes critical interleukin-2-mediated immunologic responses, but that the decidua uses nonspecific antiproliferative mechanisms for immunoregulation.

Decidua↗
PubMed2000

Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor.

Preeclampsia and fetal growth restriction are associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes diminished trophoblast differentiation and enhanced apoptosis. We tested the hypothesis that hypoxia induces apoptosis in cultured trophoblasts, and that epidermal growth factor (EGF), an enhancer of trophoblast differentiation, diminishes hypoxia-induced apoptosis. Trophoblasts isolated from placentas of term-uncomplicated human pregnancies were cultured up to 72 h in standard (PO(2) = 120 mm Hg) or hypoxic (PO(2) <15 mm Hg) conditions. Exposure to hypoxia for 24 h markedly enhanced trophoblast apoptosis as determined by DNA laddering, internucleosomal in situ DNA fragmentation, and histomorphology, as well as by the reversibility of the apoptotic process with a caspase inhibitor. Apoptosis was accompanied by increased expression of p53 and Bax and decreased expression of Bcl-2. Addition of EGF to cultured trophoblasts or exposure of more differentiated trophoblasts to hypoxia significantly lowered the level of apoptosis. We conclude that hypoxia enhances apoptosis in cultured trophoblasts by a mechanism that involves an increase in p53 and Bax expression. EGF and enhancement of cell differentiation protect against hypoxic-induced apoptosis.

Apoptosis↗
PubMedDate not supplied

Inhibition of platelet aggregation by rat trophoblasts.

OBJECTIVE: To determine the effect of rat trophoblast cell suspensions on adenosine diphosphate (ADP)-induced platelet aggregation. MATERIALS AND METHODS: The trophoblasts were isolated from ectoplacental cones (a preplacental tissue very rich in trophoblasts) developed in rat embryos on day 12 of pregnancy (normal period of gestation: 22-23 days). Platelet-rich plasma (PRP) was obtained from adult male rats. The trophoblasts were preincubated (37 degrees C, 30 min), suspended in the medium, and then re-incubated with PRP for 3-5 min. RESULTS: 5 x 10(4) and 7 x 10(4) trophoblasts inhibited ADP-induced platelet aggregation by 10 and 18%, respectively. When the trophoblast cell concentration was increased to 1-2 x 10(5) cells, a proaggregatory phenomenon was observed, even in the absence of ADP. However, there was no inhibition of aggregation or promotion of aggregation when fixed trophoblasts or live endometrial stromal cells were incubated with PRP. CONCLUSION: The results indicate that the aggregation inhibition response was cell specific and concentration dependent. A 68-kD protein was detected in the medium when it was conditioned with 5-7 x 10(4) but not with 1-2 x 10(5) trophoblasts. However, the inhibitory or stimulatory effect does not seem to be dependent on the presence of this protein.

Adenosine Diphosphate↗
PubMed2005

Signal transduction in trophoblast invasion.

During the first trimester of pregnancy, well-differentiated primary cells of the placenta known as trophoblast cells grow in an invasive and destructive fashion similar to malignancies, but limited in space and time. The comparison of trophoblast cells with their malignant counterpart, human choriocarcinoma cells, offers an attractive model to understand the origin or development of malignant growth. Several cytokines and growth factors are known to influence trophoblast migration (e.g. EGF, IGF-2, HGF), proliferation (e.g. leptin, HGF, GM-CSF) and/or invasion (e.g. leukemia inhibitory factor, LIF), each factor utilizing at least one pathway for intracellular signaling in the trophoblast. Two pathways that are crossed especially often mediate the signals of these factors and are simultaneously well established in terms of tumor invasion: the Janus kinase-signal transducers and activators of transcription (Jak-Stat) and receptor-associated tyrosine kinase-mitogen-activated protein kinase (RTK-MAPK) pathways. These two pathways are detrimental for reproduction in general, and in part for placenta development, as a series of knockout experiments demonstrate. Aspects of each pathway are also implicated to be involved in trophoblast invasion, e.g. STAT3 is constitutively activated in invasive first trimester trophoblast cells, and activated ERK is detectable in intermediate trophoblast cells, an invasive phenotype. Interaction at several intersection points between the pathways has been described in several cell systems so that the same would seem to be possible in trophoblast cells. In this review, some of the possible areas of interaction are alluded to.

Animals↗