Human Reproduction Update Advance Access published online on April 17, 2008
Human Reproduction Update, doi:10.1093/humupd/dmn010
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Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3)
Klinik für Frauenheilkunde und Geburtshilfe, Abteilung für Geburtshilfe, Placenta-Labor, Friedrich-Schiller-Universität Jena, Bachstr. 18, 07743 Jena, Germany
To whom correspondence should be addressed at: 1 Correspondence address. Tel: +49-3641-933763; Fax: +49-3641-933764; E-mail: markert{at}med.uni-jena.de, www.placenta-labor.de
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Abstract |
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Trophoblast cells display a very unique capability: they physiologically invade into the surrounding tissue. This capability is widely associated with tumours, and, indeed, the invasive behaviour of both is rather similar. The imposing difference is that trophoblast cell invasion is temporally and locally controlled in contrast to unlimited tumour invasion. It initiates immediately after embryo implantation into the endometrium. Parallel to tumours, trophoblasts secrete proteases, such as matrix metalloproteinases, which dissolve the extracellular matrix and the surrounding tissue. Thereby, these proteases prepare and allow true invasion of trophoblasts. The invasive capacities of trophoblasts are positively and negatively regulated by numerous cytokines including leukaemia inhibitory factor (LIF), interleukin-6, hepatocyte growth factor, granulocyte macrophage–colony stimulating factor and others. They interact via specific receptors with the trophoblast cells, in which they activate intracellular signalling cascades. These will then induce expression of invasion relevant genes. One of these signalling pathways is the Janus kinase/signal transducers and activators of transcription (STAT) pathway. Especially phosphorylated STAT3 enhances invasiveness of tumours and trophoblast cells, where it is mainly activated by LIF. One of its most efficient physiological antagonists is suppressor of cytokine signalling 3. The balance of these two intracellular molecules seems to be a key regulator of tumour and trophoblast invasion.
Key words: trophoblast cells / trophoblast invasion / STAT3 / supressor of cytokine signalling 3 / LIF
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Introduction |
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Trophoblast cells are capable of invasion processes that are seen also in malignancies with the exception that trophoblast cells are physiological cells that grow invasively in a completely physiological setting (Kliman, 1993
; Koldovsky, 1999; Murray and Lessey, 1999; Bischof et al., 2000) and, impairment of this type of invasion can result in pregnancy related pathologies. Furthermore, trophoblast cells are able to mask or protect themselves from the maternal immune system and thus escape potentially detrimental immunological responses stemming from the mother. Cancerous tumour cells abuse and mimic these characteristics to the disadvantage of the affected ‘host’. These two characteristics make trophoblast cells exceptional in comparison to other physiological cells in that they may pose as an exciting model in investigating the process of invasion. As the physiological and pathological settings lie in close proximity to each other, the deregulative progression may be better analysed. Especially intracellular processes, such as signal transduction, are an attractive field to explore since it seems that trophoblast cells themselves control their invasive growth in space and time (mainly limited to the first trimester and the decidua) at least to some degree. This may be seen in the situation of trophoblast cells originating from extrauterine or xenogeneic gravidities since these cells are just as capable of invasion as the trophoblast of regular pregnancies (Randall, 1986; Poehlmann et al., 2004). Any boundary seen here is usually found in physical limitations.
Another point of interest is the effects of local cytokines, produced either by trophoblast themselves or by other surrounding cells (Fitzgerald et al., 2005a,b,c; Makrigiannakis et al., 2006). These cytokines are often able to control trophoblast behaviour in some way, by either modulating proliferation and migration or inducing trophoblast to differentiate into an (non-)invasive phenotype. All of these cytokines use various intracellular signal mediating pathways. Some of these mechanisms have been explored by several groups, but we are yet far from understanding the whole picture. The signalling pathways of some cytokines are still not completely illuminated. Exact mechanisms, particularly in respect to possible crosstalk, are only partially understood.
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Early trophoblast development |
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The differentiation of the trophectoderm into two separate trophoblast subsets takes place immediately prior to invasion into the decidual matrix, but seems to be triggered by the process of adhesion (Armant, 2005
). Initially, the outer trophoblast phenotype, the syncytiotrophoblast, invades the maternal endometrium lining to create a cavity into which the blastocyst may embed (Bischof and Campana, 1997). The capacity of syncytiotrophoblast to invade the decidual matrix is lost after implantation. Following this period, cytotrophoblast, which are considered trophoblast stem cells, supply a replenishment of trophoblast of the invasive phenotype, while the syncytiotrophoblast panel the chorionic villi and intervillous space and take over a more endocrinological task. Trophoblasts existing outside of this intervillous space are termed extravillous trophoblasts and have acquired the invasive phenotype, in order either to anchor chorionic villi into the Nitabuch layer or to profoundly infiltrate the decidua, reach maternal spiral arteries and arrode them. The direction of invasion seems to be determined through the expression of integrins of the decidual matrix surrounding the trophoblast cell and the capacity of this cell to produce matrix metalloproteinase (MMP) (Bischof and Campana, 2000).
Trophoblast cells of the implanting blastocyst also participate in a cyclic endocrinological process by producing human chorionic gonadotropin (hCG), which in turn converts the corpus luteum of the menstrual cycle to the progesterone producing corpus luteum of pregnancy that promotes decidualization, protects gravidity, as well as supports the development of the embryo. Progesterone is involved in immunosuppression at the feto–maternal interface and thereby protects the fetus further from unwanted immunological responses (Szekeres-Bartho et al., 2005).
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Implantation |
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Implantation of the human blastocyst, and the event of trophoblast invasion that accompanies this process, is considered by some to be the major time limiting factor for the establishment of pregnancy (Herrler et al., 2003
). Implantation begins with the apposition and attachment of the blastocyst to the uterine mucosa (Fig. 1). At this time, the blastocyst is composed of a 5-cell inner cell mass and surrounded by a 53-cell trophoblast hull, the trophectoderm, which is destined to differentiate into the placenta. Here, initial cell-to-cell contact is recognizable through the adherence of the apical plasma membranes of trophoblast and uterine epithelium (Enders and Mead, 1996). Normally, epithelial cells do not allow adhesion of other cells to their apical surface making trophoblast–uterine epithelial attachment a unique circumstance (Hohn and Denker, 2002).
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An excellent and quite detailed description of the implantation window, as well as the development of the invasive trophoblast can be found recently reviewed in this journal by Ferretti et al. (2007
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The implantation window is understood to be the period of maximal uterine receptivity, and is believed to commence 7 days after ovulation (around Day 20 of an idealized 28-day cycle) and lasts no more than 2 days (Cavagna and Mantese, 2003). Several biological markers implicated in disclosing the implantation window by ‘dating’ the endometrium have attracted attention in recent years (Fig. 1).
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Invasion promoting cytokines |
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The focus of investigation has often been directed on the occurrence of cytokines during the complex event of placentation. It is known that migration and invasion of extravillous trophoblast cells are functionally controlled by a plethora of cytokines and growth factors, but the relevance of individual cytokine-induced signalling processes is still under elucidated.
One of the most important candidate pathways seems to be the Janus kinase–signal transducer and activator of transcription (JAK–STAT) cytokine signal transducing pathway. Several cytokines that are important to reproductive medicine are known to signal through this pathway in other cells. Below is a synopsis of some of the most prominent of these cytokines and growth factors, and their influence on the reproductive field (Table I).
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Hepatocyte growth factor
The morphogenic hepatocyte growth factor (HGF) has been described in mediating motility in tumours by activating STAT3 (a member of the JAK–STAT signal transduction pathway, as will be alluded to later). It seems that HGF is expressed by placental stromal cells, while the receptor is located on the trophoblast (Saito et al., 1995). Furthermore, HGF is known to arbitrate the invasive potential of trophoblast cells since trophoblast invasion is dose-dependently increased by HGF (Kauma et al., 1999). HGF knockout experiments in the mouse model have revealed that expression deficiency leads to lethal placental failure due to a complete lack of development of labyrinthine trophoblast (Schmidt et al., 1995; Uehara et al., 1995). All of these facts hint that HGF is of fundamental importance in the mesenchymal induction of trophoblast growth and differentiation during the development of the placenta (Stewart, 1996). Lack of HGF has even been advocated in causing pre-eclampsia in human pregnancies since the placentae from pre-eclamptic women were associated with a decreased HGF production (Kauma et al., 1999). Finally, an altered expression of HGF and STAT3 has been described in the placental tissues of malformed fetuses (Trovato et al., 2002).
A further cytokine that utilizes STATs to mediate its signal is IL-6. IL-6 is a cytokine that is correlated with a higher metastatic potential of cancer cells when found in the serum of cancer patients, at least in the head and neck. IL-6 enhanced the invasiveness of head and neck cancer cells (Nishino et al., 1998) and ovarian cancer cells (Obata et al., 1997). In human choriocarcinoma, IL-6 failed to stimulate cell growth in cultures, but knocking out of IL-6 resulted in inhibiting cell growth (Kong et al., 1996). Moreover, IL-6 found in the amniotic fluids of early pregnancy seems to be produced by trophoblast cells (Jauniaux et al., 1996). This concentration could be positively correlated to gestational age. Cytotrophoblast cells, which are the invasive phenotype, express high levels of IL-6 (Das et al., 2002) and increase the activity of MMP-9 and MMP-2, both important proteins in invasion and implantation (Meisser et al., 1999). Maximum IL-6 mRNA and protein expression is identified in the human endometrium at the time of implantation (Tabibzadeh et al., 1995; Vandermolen and Gu, 1996) and its receptor is present on both maternal (endometrial epithelial cells) and fetal tissues (trophoblast and blastocyst) during implantation and placentation (Kojima et al., 1995; Sharkey et al., 1995; Tabibzadeh et al., 1995). However, it seems that IL-6-deficient female mice are fertile with normal litter sizes and no significant difference in implantation rates similar to control groups (Bluethmann et al., 1994), although IL-6 and LIF share gp130 as a common signal transducing molecule (see below). This cytokine induced an increased expression of integrins associated with embryo attachment and its production could be hemmed by hCG and progesterone (Das et al., 2002). Reduced expression of IL-6 was found during the secretory phase endometrium of women with recurrent miscarriage (Jasper et al., 2007).
IL-11 is another cytokine of the ‘IL-6 cytokine family’ and this conveys its signal through the same pathway. Female mice with a null mutation of the IL-11 receptor 
-chain are infertile because of defective decidualization, which apparently leads to uncontrollable trophoblast invasion (Bilinski et al., 1998; Robb et al., 1998). The same receptor subunit has been detected on developing decidual cells. IL-11 expression is at a maximum at the time of decidualization in the human gravid uterus (Dimitriadis et al., 2000). IL-11, its receptor and LIF (see below) are dysregulated in the endometrium of infertile women with endometriosis during the implantation window (Dimitriadis et al., 2006a,b). Furthermore, the production of IL-11 and decidualization are compromised in endometrial stromal cells derived from patients with infertility (Karpovich et al., 2005). These results are consistent with the possibility of a paracrine mechanism between uterus and decidua for STAT3 activation. As a matter of fact, a recent study suggests that IL-11-induced signalling initiates and maintains the decidualization process through STAT3 and suppressor of cytokine signalling (SOCS3) activation (Dimitriadis et al., 2006a,b).
Concerning trophoblast cells, it could be demonstrated that the IL-11 receptor is found on interstitial, or invasive/migratory, trophoblast cells. Furthermore, this cytokine is able to boost the migration of human trophoblast cells without altering the rate of its proliferation and that this feat is probably accomplished through stimulation of STAT3 phosphorylation (Paiva et al., 2007).
LIF has been proposed to be indispensable during placentation in several species (Stewart and Cullinan, 1997; Vogiagis and Salamonsen, 1999). LIF-deficient mice, though not sterile, are infertile and fertility may be restored through infusion of LIF into the uterus (Stewart et al., 1992). The fact that these LIF –/– blastocysts are able to implant in pseudopregnant wild-type mice indicates that maternal LIF deficiency prevents implantation in this case. The blastocysts of LIF receptor knockout (KO) mice implant, but die within 24 h of birth due to impaired placenta function (Ware et al., 1995). LIF is assumed to facilitate implantation since LIF is present at high amounts in the maternal–fetal interface and because it is produced by both the human placenta and endometrium (Cullinan et al., 1996; Kondera-Anasz et al., 2004), where it is maximally expressed at the time of implantation (Bhatt et al., 1991). LIF receptors are present on the trophoblast (Kojima et al., 1995) and trophoblast cells are thus controllable. During the implantation window, the embryo or blastocyst expresses mRNA for the LIF receptor and then produces LIF mRNA itself (Charnock-Jones et al., 1994; Sharkey et al., 1995; van Eijk et al., 1996; Chen et al., 1999). When the blastocyst invades the luminal epithelium and thus reaches the stroma, it begins to synthesize cytokines such as IL-1, which in turn induces LIF expression in the endometrium (Fig. 1) (Simon et al., 1994a,b; Laird et al., 2000; Aghajanova, 2004).
Human choriocarcinoma cells increase regulation of HLA-G, a non-classic class I MHC molecule believed to be involved in the ‘masking’ of the cell from the immune system, in response to LIF (Bamberger et al., 2000). In addition, LIF could promote the proliferation and invasion of choriocarcinoma cells and trophoblast cells (Fitzgerald et al., 2005a,b,c). Knock down of STAT3 in both cell types resulted in loss of LIF mediated invasion (Poehlmann et al., 2005). It has been proposed that decidual natural killer cells might regulate invading trophoblast cells as they encounter them in the decidua by secreting LIF (Sharkey et al., 1999). LIF suppresses its own effects by means of a negative feedback mechanism on the JAK–STAT pathway (Naka et al., 1997). In this context, both too low and too high levels of LIF in uterine flushings have been suggested to have negative predictive value in implantation success (Laird et al., 1997; Ledee-Bataille et al., 2002).
Granulocyte macrophage–colony stimulating factor
GM–CSF, though not of the IL-6 type family, is also a mediator that uses the JAK–STAT pathway. GM–CSF promotes DNA proliferation, differentiation and secretory activity of human and mouse cytotrophoblast cells in vitro (Athanassakis et al., 1987; Armstrong and Chaouat, 1989) and thus probably functionally supports the development of the placenta. Estrogen regulates the synthesis of GM–CSF by uterine epithelial cells in mice, sheep and humans (Robertson and Seamark, 1992; Imakawa et al., 1993; Giacomini et al., 1995). Even small amounts of exogenous GM–CSF administered to mice dramatically alters pregnancy outcome (Chaouat et al., 1990; Tartakovsky et al., 1991). In GM–CSF-deficient mice, fetal growth and viability were jeopardized due to compromised placental function. These effects were increasingly deleterious when the conceptus was also deficient, suggesting that GM–CSF of either maternal or fetal origin is required for optimal fetal growth and survival (Robertson et al., 1999). One group could show that GM–CSF concentration in the peripherous blood of pregnant patients suffering from unexplained recurrent abortion was significantly reduced (Perricone et al., 2003).
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Regulation of invasion at the intracellular level |
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The JAKs–STAT pathway
Regulation of invasion may occur not only on the extracellular level, through cytokines, but also on the intracellular level. This will be demonstrated on the example of JAK–STAT signalling pathway and the trophoblast cell and its malignant derivates, the human choriocarcinoma cell.
Briefly (as illustrated in Fig. 2), receptors aggregate upon cytokine binding, which leads to the juxtaposition of receptor associated tyrosine kinases called Janus kinases or JAKs (named after the two-headed Roman mythological god, Janus, because of its ‘two-headed’ structure). These JAKs are now enabled to cross-phosphorylate and activate each other, as well as specific domains on the cytoplasmic domains of their respective cytokine receptor. In doing so, intracellular STATs are now capable of binding to these receptor domains, so the STATs may also in turn be phosphorylated and activated by the JAKs. Upon activation, the STATs disassociate from the receptor and proceed to form homo- and heterodimers that translocate into the nucleus of a cell. Here, the STATs up-regulate or accelerate the transcription of target proteins by binding and influencing the promoter regions of these proteins. One of the transcribed proteins is the SOCS protein, a regulator that is specifically and non-specifically able to negatively modulate the duration of the cytokine signalling response by binding to phosphotyrosine residues as seen for instance on JAKs (Kamura et al., 1998; Hilton, 1999).
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Gp130, JAKs and STAT in knockout models—lessons for reproduction
Disruption of gp130, the STAT3-activating subunit shared by all members of the IL-6 receptor family, leads to an identical phenotype as knocking out of LIF (Ernst et al., 2001). It has also been found that endometrial secretion of soluble gp130 (sgp130) is increased multifold during the implantation window and that this secretion appears to be reduced in infertile patients (Sherwin et al., 2002). Interestingly, sgp130 blocks the biological activity of LIF and IL-6 (Montero-Julian et al., 1997; Muller-Newen et al., 1998; Zhang et al., 1998).
IL-6, and IL-6 type cytokines, leads to the activation of JAK1, JAK2 and TYK2 (Heinrich et al., 1998). As reviewed by Yamaoka et al. (2004), most Jak- or Tyk-KO mice are fertile and produce viable phenotypes, but two interesting exceptions are noted here. Jak1–/– mice are viable yet weigh 40% less than their heterozygote littermates, and die perinatally due to neurological deficits that encumbers suckling. A remarkable insight is seen in the fact that the Jak1 KO mouse differs from the phenotype observed in gp130 disrupted mice, but resembles the phenotype of mice lacking the LIF-receptor subunit β (Rodig et al., 1998).
Deficiency of Jak2 results in embryonic lethality at Day 12.5, but this is due to a failure in erythropoiesis. No pathology concerning the placentas of these pregnancies was reported (Neubauer et al., 1998).
As Akira (1999) and Heinrich et al. (1998) beautifully review, the effects of Stat deficiency in mice do not usually include impairment of fertility, implantation or embryo development, with the exception of these two cases.
All of the above mentioned cytokines share STAT3 as a common constituent of their intracellular signal transduction pathways and also seem to have a positive influence on the invasion, proliferation and/or differentiation of trophoblast cells, thus facilitating pregnancy-related events, i.e. implantation.
Numerous reports indicate that STAT3 plays a role in reproduction. Evidently, as STAT3 is activated during the early post-implantation period of the mouse and is essential for embryogenesis, STAT3 is indispensable to murine pregnancy. Wild-type mouse embryos express STAT3 on the extra-embryonic visceral endoderm 7.5 days post-coitum. Concurrent to this, STAT3 –/– mice degenerate and die, but can be rescued through substitution with an alternative splice form of STAT3, STAT3β, in which the C-terminal transactivation domain is replaced with a seven amino acid extension (Duncan et al., 1997; Takeda et al., 1997; Akira, 1999). Furthermore, the inhibition of STAT3 activation in the endometrium of the mouse was shown to prevent implantation (Catalano et al., 2005).
STAT5 consists of two highly related genes encoding STAT5a and STAT5b, and was originally identified as a transcription factor in mammary gland tissue whose phosphorylation is induced by prolactin (Schmitt-Ney et al., 1992).
Especially STAT5b null mice showed signs of impaired fertility as females consistently aborted between Days 8–17 of pregnancy (Udy et al., 1997). In this study, no obvious maternal, placental or fetal defect could be detected, but s.c. application of progesterone maintained pregnancy to term. In a further study, the deletion of STAT5a/b in mutant female mice resulted in infertility (Teglund et al., 1998). Evidently, the cause of this infertility could be distinguished in the ovaries of these animals, since, although ovulation occurred normally, they were lacking in large corpora lutea. The main site of STAT5a/b expression appeared to take place directly in the corpora lutea and not in developing or mature follicles.
Prolactin induces follicular granulosa cells to differentiate into a functioning corpus luteum, in other words one that produces adequate pregnancy-sustaining progesterone. In this context, it is tempting to speculate that STAT5a/b-deficient infertility is due implantation failure or placental insufficiency on the basis of progesterone shortage.
As mentioned earlier, the mechanistical similarity between invasiveness of trophoblast and cancer cells invites the sharing of knowledge from one field to the other. The process of tumour invasion involves the activity of signal mediators triggered by STAT3. Aberrant activity of phosphorylated, dimerized STAT3 is advocated to be causal for neoplastic cell behaviour, such as hyperplasia, longevity or invasion, and thus for the malignancy of cells (Bromberg et al., 1999). Indeed, constitutively activated STAT3 has been found in a number of tumours (Bowman et al., 2000).
STAT3 appears to play an essential role in the organization of motility in various types of tumour and pluripotent cells (Boccaccio et al., 1998; Yeung et al., 1998; Zhang et al., 2002). Moreover, STAT3 has been implicated in the transcriptional regulation of proteases, a process with crucial importance for invasive cellular growth (Smola-Hess et al., 2001; Puricelli et al., 2002; Udayakumar et al., 2002).
Various reports indicate the influence of STAT3 on cellular growth behaviour (reviewed in Buettner et al., 2002). Cell transformation by aberrant STAT3 activity in tumours probably involves up-regulation of genes promoting cell cycle progression (cyclin D1, c-myc) and/or preventing apoptosis (bcl-xL; mcl-1; survivin) (Bromberg et al., 1999; Epling-Burnette et al., 2001; Shen et al., 2001).
Using Jeg-3 human choriocarcinoma cells, as an easily controllable model for invasive, first trimester trophoblast cells, recent findings suggest the possibility that STAT3 is a central player in pathways triggered by diverse factors that modulate placentation (Fitzgerald et al., 2005a,b). These findings indicate a causal connection of LIF-driven STAT3 activity and an altered protease expression pattern in Jeg-3 choriocarcinoma cells. Interestingly, the two proteases whose mRNA levels were influenced by LIF-dependent STAT3 activation have been described to contribute to invasive cell behaviour or implantation: Tissue inhibitor of metalloproteinase (TIMP)-1 expression was found down-regulated in response to LIF, and caspase-4, formerly termed IL-1β converting enzyme homologue 2 (ICH-2), was up-regulated (Fitzgerald et al., 2005a,b). TIMP-1 is linked to inhibition of metastasis (Bischof et al., 2001). In choriocarcinoma cells, its expression was found to be reduced due to genetic changes and this down-regulation was correlated with the hyperinvasive and malignant phenotype (Lala et al., 2002). It is conceivable to assume that TIMP-1 expression is directly influenced by STAT3, since STAT3-driven TIMP-1 regulation was also described in other cell types such as synovial lining cells and hepatocytes (Gatsios et al., 1996; Richards et al., 1997) and the TIMP-1 promoter was shown to contain STAT3 recognition elements (Richards et al., 1997). Caspase-4 generates the bioactive form of IL-1β (Kamens et al., 1995). Its expression is low in all human tissue except in ovaries and it is secreted by preimplantation mouse embryos. The importance of IL-1 processing by caspase-4 in implantation is underscored by the fact that the IL-1 receptor is maximally expressed in the endometrium during the secretory phase and that the IL-1 receptor antagonist evokes a lower rate of (murine) implantation (Simon et al., 1994a,b).
Immunoreactive IL-1β is present in the villous cytotrophoblast, syncytiotrophoblast and intermediate trophoblast (Simon et al., 1994a, b) and apparently suppresses, at least in endometrial stromal cells, the expression of TIMP-1 mRNA (Huang et al., 1998). Furthermore, TIMP-1 inhibits all MMPs in an activated form, but preferentially binds to latent and active MMP-9 (Goldberg et al., 1992), which has been found to be critical for cytotrophoblast invasion (Librach et al., 1991). Whether this could be indicative of an autocrine regulation requires further investigation.
Moreover, LIF promotes giant cell differentiation in vitro and in vivo, with giant cells being murine epithelial trophectoderm cells that have transformed into an invasive population at the time of implantation. This differentiation is apparently contained through negative regulation via SOCS3 proteins which suppress the JAK–STAT signal transducing pathway and is induced by a broad spectrum of cytokines, including LIF (Starr et al., 1997; Sutherland, 2003; Takahashi et al., 2003).
There are two splice forms of STAT3, and β, whose potential functional differences are currently the subject of intense research. When both isoforms were overexpressed in Cos (monkey fibroblast) cells, only STAT3β was constitutively able to cooperate with c-Jun, another oncogenic transcription factor (Schaefer et al., 1995). On the one hand, STAT3β was described to be a dominant negative regulator of STAT3, on the other hand, STAT3-deficient mice can be rescued by STAT3β (Caldenhoven et al., 1996; Yoo et al., 2002; Maritano et al., 2004). Interestingly, a high activation level of STAT3β was observed in the HCC cell line JAR in contrast to first trimester and term trophoblasts (Corvinus et al., 2003). The role of STAT3β in choriocarcinoma will have to be investigated, since it may provide the opportunity to identify specific STAT3β target genes. It will be of particular importance to characterize the mechanisms that limit and cease STAT3 activity in trophoblasts. This regulation may occur via above mentioned inhibitors of STAT signalling such as SOCS or PIAS (protein inhibitor of activated STATs) (Hilton, 1999), by receptor down-regulation or through the loss of cytokine secretion. The dysregulation of STAT3 activity patterns during placental development might provoke pathological processes such as diseases related to defective placentation, hypoinvasion in pre-eclampsia or neoplasms like human choriocarcinoma (Tarrade et al., 2002). A better understanding of STAT function during placentation may lead to novel molecular and pharmacological strategies to interfere with signalling processes (Buettner et al., 2002).
As reviewed by Boyle and Robb, the Socs3 KO mouse model demonstrates that a lack of this gene leads to placental insufficiency, and ultimately, embryonic lethality around embryonic Day 13 (Marine et al., 1999; Roberts et al., 2001; Takahashi et al., 2003; Boyle and Robb, 2008). The highest rates for SOCS3 expression could be found in cells surrounding the chorionic plate, in labyrinthine, spongiotrophoblast and trophoblast giant cells or in short, cells known amongst others for invasive capacity. These embryos were rescued successfully upon supplementation with wild-type extraembryonic tissues capable of SOCS3 compensation (Takahashi et al., 2003, 2006). Interestingly, the defects of Socs3-null placentae were counteracted by deleting the LIF-receptor -chain (Takahashi et al., 2003). Another group was able to confirm that STAT3 mediates the constitutive expression of SOCS3 (Isobe et al., 2006).
In the human, SOCS proteins, especially nuclear, were immunolocalized to the syncytiotrophoblast (Keelan et al., 2003; Blumenstein et al., 2005). It has been postulated that decreased SOCS activity in human gestational tissues may play a part in the onset or progression of term, yet overexpression of SOCS in pre-term, labour. Considering the fact that activated peripheral blood mononuclear cells induce the phosphorylation of STAT1 and STAT3 in human trophoblast cells (Jiang et al., 2007), it seems possible that inflammatory cytokines as often found in infections causative to pre-term labour may be responsible for this elevation of SOCS expression.
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Conclusion |
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The current literature on functions of STAT3 in human trophoblast cells indicates its involvement in regulation of invasiveness. Several soluble factors which are generally present in the decidua, mainly HGF, GM–CSF, IL-6, IL-11 and LIF, have been described to use JAK–STAT pathways for signalling and may thereby influence invasiveness. The knowledge about the role of the STAT3 negative regulator SOCS3 is very preliminary, but an invasion controlling role may be expected.
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Funding |
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The group is funded member of ‘EMBIC’ (Embryo Implantation Control; www.embic.org), an European Network of Excellence within the 6th Framework Programme of the European Union (Contract no. 512040).
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