Mol. Hum. Reprod. Advance Access originally published online on May 19, 2006
Molecular Human Reproduction 2006 12(7):413-419; doi:10.1093/molehr/gal045
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Novel function of ovarian growth factors: combined studies by DNA microarray, biochemical and physiological approaches
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot and 2Department of Obstetrics and Gynecology, IVF Unit, Assaf Harofeh Medical Centre, Tel-Aviv University, Zerifin, Israel
3 To whom correspondence should be addressed at: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel. E-mail: abraham.amsterdam{at}weizmann.ac.il
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Abstract |
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 Top Abstract IntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Owing to the development of the DNA microarray technique, modulation of gene function can be studied systematically. Considerable attention has been focused on members of the growth factor family to elucidate the main regulators of oocyte maturation and ovarian follicle rupture. Among these growth factors, it was found both in rodents and in humans that amphiregulin (Ar) and epiregulin (Ep) of the epidermal growth factor (EGF) family were dramatically up-regulated by gonadotrophins in the intact ovary and in primary granulosa cells, respectively. Their role in cumulus expansion and oocyte maturation was established in rodents, and their formation under LH stimulation in granulosa cells was demonstrated in humans. To be activated, Ar and Ep must be cleaved by A Disintegrin And Metalloproteinases (ADAMs) family. However, the precise processing of Ar and Ep by the cumulus cells is still obscure. Future investigations using DNA microarray technique may reveal the repertoire of genes activated in Ar- and Ep-stimulated cumulus cells and may help elucidate the molecular basis of ovulation.
Key words: amphiregulin/EGF-like growth factors/epiregulin/metalloproteinase/oocyte maturation
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Introduction |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Growth factors are polypeptides that modulate cell proliferation and differentiation. They act through binding to specific cell membrane receptors. In contrast to classic endocrine substances, they act locally and function in paracrine and autocrine modes.
Traditionally, studies examining the control of ovarian follicular development and oocyte maturation have focused mainly on the endocrine regulation of the hypothalamic–pituitary–ovarian axis. However, it has long been recognized that intraovarian factors are also important in regulating follicular development in a paracrine or an autocrine manner (Juengel and McNatty, 2005
). In recent years, considerable attention has been focused on members of the growth factor families in controlling oocyte maturation and ovulation.
Although intensive and extensive research has been conducted over years to decipher the main factors that cause oocyte maturation and ovarian follicle rupture, an extensive spectrum of genes modulated in response to gonadotrophin stimulus in isolated human granulosa cells has only recently been described (Sasson et al., 2004). Previous studies revealed the changes in gene expression either in intact rat ovary (Leo et al., 2001) or in isolated mouse ovarian follicle (Liu et al., 2001). However, because the intact ovary is composed of different types of cells and tissues, which may contain heterogeneous repertoire of actively expressed genes, we used primary granulosa cells obtained from women undergoing IVF treatment because of male infertility. Following stimulation with LH, FSH and forskolin (FK), up-regulation of gene transcripts coding to growth factors and growth factor receptors and down-regulation of growth-arrest factors were observed using DNA microarray that contains the entire human genome (Table I, Rimon et al., 2004).
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Insulin-like growth factors |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Previously termed somatomedins, insulin-like growth factors (IGFs) are peptides that share structural and functional similarities with insulin and mediate growth hormone action (reviewed in Giudice, 1992
).
IGF-2 is the primary IGF in the human ovary. It is capable of stimulating steroidogenesis and proliferation in human granulosa and theca cells (Di Blasio et al., 1994; Mason et al., 1994). We found (Table I), using DNA microarray, a dramatic elevation in gene transcripts of IGF-2 and its receptor (IGF2R). Interestingly, although the increase in IGF-2 is cyclic AMP (c-AMP) dependent, the increase in IGF2R seems to be c-AMP independent (Table I).
The IGF-binding proteins (IGFBP) are six non-glycosylated peptides, which serve as IGF carriers in the serum, prolong their half-lives and regulate their tissue effects. This regulation is achieved by binding and sequestering of the IGFs, thus preventing their access to the cell membrane surface receptors (Giudice, 1992). A functional relationship between the IGF system and FSH action has been established by the finding that IGFBP-4 is a potent inhibitor of FSH-induced estradiol biosynthesis by human granulosa cells (Mason et al., 1998). Although the mechanism underlying the IGFBP-4 inhibition of FSH action remains to be elucidated, it appears to involve neutralization of intrinsic IGF bioactivity, such as IGF-2 in human (reviewed in Erickson and Shimasaki, 2001). Although we found a decrease in the gene transcripts of IGFBP-2 (Table I), which was expected because of the inhibitory effect of gonadotrophins on its expression in granulosa cells (Liu et al., 2002), a pronounced elevation in IGFBP-4 was recorded in response to FSH and LH in a c-AMP-dependent manner. Because IGFBP-4 is elevated more than 20 times by c-AMP than LH or FSH, alternative factors other than gonadotrophins may be involved. In view of the inhibitory effect of IGFBP-4 in response to IGF-2–IGF2R interaction (Wright et al., 2002), IGFBP-4 activity could counteract the elevation of IGF-2 receptors.
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Transforming growth factors |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Although transforming growth factor-
(TGF-) is structurally analogous to epidermal growth factor (EGF) and can bind to its receptor, TGF-ß utilizes a different receptor. Both are considered as autocrine growth regulators. TGF-, like EGF, stimulates oocyte nuclear and cytoplasmic maturation (Reeka et al., 1998). TGF-ß, which is secreted by theca cells, enhances LH receptor production by granulosa cells in response to FSH stimulation (Dodson and Schomberg, 1987), whereas it inhibits androgen production by theca cells (Hernandez et al., 1990). TGF-ß was found to control proliferation of epithelial cells and may be involved in recruitment and development of the follicle (reviewed in Findlay et al., 2002), whereas a mutation in TGF receptors may be involved in cancer development (Francis-Thickpenny et al., 2001). TGF-ß sub-family is known to be secreted as a latent protein, consisting of the TGF-ß mature region dimer non-covalently associated with a dimer of the proregion that is covalently associated with a latent TGF-ß binding (reviewed in Juengel and McNatty, 2005). Removal of these latent binding proteins is necessary for TGF-ß activation, as they inhibit the biological activity of the TGF-ß (reviewed in Olofsson et al., 1997). Gene transcripts to TGF-ß type III receptor were up-regulated by LH and FSH stimulation, whereas those coding for latent TGF-ß-binding protein 2 (LTBP2) were down-regulated (Table I). Because TGF-ß type III receptor up-regulation was higher by LH than by FSH stimulation and because FK stimulation did not change its level, it seems to be c-AMP independent.
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Vascular endothelial growth factor |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Vascularization of the follicle is influenced by peptides in the follicular fluid, especially vascular endothelial growth factor (VEGF). During folliculogenesis, VEGF expression in growing ovarian follicles is induced by gonadotrophins and accompanied by an increased vascular network in the thecal cell layer (reviewed in Lam and Hines, 2005
). VEGF secreted by thecal cells increases vascular permeability (Levin et al., 1998), thus facilitating extravasation of plasma and the accumulation of antral fluid in the growing follicles (Kamat et al., 1995). The increased vascular permeability enhances the delivery of mediators such as lipids, which are used as precursors for androgen synthesis in thecal cells. These thecal androgens are then aromatized in the avascular granulosa cell layer to form estrogen. Binding of VEGF to its receptors is dependent on cell surface-associated heparin-like molecules (Gitay-Goren et al., 1992). Interference of this binding results in suppression of thecal angiogenesis and inhibition of follicular growth and development (Wulff et al., 2002).
Our data from DNA microarray studies show that following LH stimulation, gene transcripts to VEGF were up-regulated more than twice than by FSH stimulation (Table I). This is in agreement with the known high responsiveness of luteal cells to HCG with greater VEGF output, which contributes to the increased vascular permeability upon excess administration of HCG during IVF treatment (reviewed in Geva and Jaffe, 2000). Excessive VEGF production, as a result of exogenous gonadotrophins, may have a role in the pathogenesis of ovarian hyperstimulation syndrome (Lee et al., 1997).
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Connective tissue growth factor |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Connective tissue growth factor (CTGF) is a member of the CTGF/cysteine-rich 61/nephromblastoma overexpressed family of genes that consists of six distinct members encoding proteins that take part in essential biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, angiogenesis as well as several pathologies including fibrosis and tumorigenesis (reviewed in Harlow and Hillier, 2002
; Wandji et al., 2000). It was found to be involved in various stages of porcine folliculogenesis. CTGF mRNA biosynthesis was found to be maximal in mid-antral follicles but was down-regulated in pre-ovulatory follicles. A functional link between CTGF and lysyl oxidase genes expression was found in granulosa cells during early stages of antral follicular development (Slee et al., 2001). This was consistent with connective tissue biosynthesis and extracellular matrix deposition occurring concurrently in the ovary (Harlow and Hillier, 2002).
Stimulation of granulosa cells by FSH both in vitro and in vivo induces follicular maturation associated with down-regulation of granulosa cell CTGF mRNA expression (Harlow et al., 2002). Furthermore, CTGF was found to be present in human corpus luteum and to have a developmental role in luteal vasculature and tissue remodelling associated with luteolysis. It is inhibited by HCG during early pregnancy, and this inhibition appears to be mediated by paracrine factors (Duncan et al., 2005).
The down-regulation of CTGF gene transcript found in human granulosa cells is in line with the previous findings (Table I). Because FK dramatically decreased CTGF gene transcript and in the light of the fact that PGE2 and c-AMP were shown to modulate CTGF gene expression in rat fibroblasts (Yu et al., 2002), it was suggested that other c-AMP-dependent signals, other than gonadotrophin dependent, might participate in this down-regulation (Rimon et al., 2004).
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EGF-like growth factors |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Of all ovarian growth factors, it seems that EGF-like factors have drawn considerable attention in recent years, reflecting the discovery of their crucial role in reproduction. EGF is a member of a large group of closely related proteins that include TGF-
, amphiregulin (Ar), epiregulin (Ep), betacellulin, epigen, neuregulins and heparin-binding EGF-like growth factor. Initially, it was found two decades ago that EGF has the potential to induce expansion of the cumulus cells surrounding the oocyte in rats (Dekel and Sherizly, 1985). Thereafter, EGF was found to play a positive role in various mammalian in vitro systems of oocyte maturation (Downs, 1989; Harper and Bracket, 1993; Coskun and Lin, 1995; Lonergan et al., 1996; Lorenzo et al., 1996). However, it was not considered as an integral part of gonadotrophin-induced ovulation in normal cycling female rats. It was also shown to induce germinal vesicle breakdown and nuclear maturation when added to human germinal vesicle stage oocytes (Goud et al., 1998). Interestingly, maintenance of the cumulus during culture improved the nuclear and cytoplasmic maturation of human oocytes, suggesting an indirect effect of EGF on the oocyte. It was, therefore, puzzling that according to the DNA microarray, there was no detectable expression of EGF in human granulosa cells obtained from IVF program (unpublished data).
Nevertheless, we demonstrated a dramatic up-regulation of the EGF-like factor genes, Ar and Ep, for the first time in human granulosa cell cultures in response to LH stimulation using DNA microarray technique (Rimon et al., 2004). These data were later supported by RT–PCR technique (Freimann et al., 2005).
Initially, Ar was demonstrated in human ovarian epithelial cells (Johnson et al., 1991), while it was not detected in granulosa cells (Tamura et al., 1995). However, more recent studies have demonstrated the up-regulation of Ar and Ep genes in the rat ovary (Espey and Richards, 2002; Sekiguchi et al., 2002). Recently, it was demonstrated that incubation of germinal vesicle stage mouse follicles with Ar, Ep and betacellulin recapitulates the morphological and biochemical events triggered by LH, including cumulus expansion and oocyte maturation (Park et al., 2004). Likewise, addition of these growth factors resulted in either complete (with Ar and Ep) or partial (betacellulin) stimulation of resumption of meiosis in rat follicle-enclosed oocytes (Ashkenazi et al., 2005). It should be noted, however, that as opposed to Ar and Ep, no change in gene transcripts for betacellulin was demonstrated by us in human granulosa cell cultures following LH stimulation using DNA microarray technique (unpublished data). Similarly, it was noted that betacellulin mRNA is expressed with a time course incompatible with induction of oocyte maturation, because it accumulates well after oocyte maturation has occurred, both in vivo and in vitro (Park et al., 2004). This might indicate that this EGF-like growth factor does not take part both in mouse and in human ovulatory processes. Although it was found using DNA microarray technique that HCG administration to mouse resulted in rapid elevation of Ar and Ep mRNA, reaching maximum levels 2h after HCG injection, with a rapid decline afterwards (Conti et al., 2005), we demonstrated a different time course of Ar mRNA expression in primary human granulosa cells stimulated by LH. Using real-time quantitative RT–PCR, we demonstrated maximum levels of Ar mRNA between 2 and 8 h. Interestingly, this level was still significantly elevated even 24 h following LH administration (Figure 1).
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Ar and Ep as LH mediators
In a simplified model of mouse cumulus–oocyte complex (COC), where mural granulosa cells were removed, no cumulus expansion was observed following LH stimulation. In contrast, Ar and Ep induced cumulus expansion both in COC and in intact follicle. Interestingly, Ar and Ep were more potent in induction of cumulus expansion in COC than in the intact follicle. Furthermore, the time course of oocyte maturation, which was induced by LH stimulation of mouse oocytes, was slower than that observed with Ar and Ep (Park et al., 2004). In a similar way to that observed with EGF (Downs et al., 1988), Ar and Ep require cumulus cells to exert their effects, because denuded immature oocytes did not undergo oocyte maturation. According to the classic paradigm, c-AMP, generated by the cumulus cells, is transmitted to the oocyte via gap junctions and serves as meiotic arrestor (Dekel and Beers, 1978). It was hypothesized that the LH surge induces resumption of meiosis by the breakdown of these gap junctions, which terminates the supply of c-AMP from the cumulus cells to the oocyte (Dekel, 1988). However, because there is restricted expression of LH receptors on both the cumulus cells and the oocyte itself, many LH effects are thought to be indirect (Amsterdam et al., 1975; Peng et al., 1991). Furthermore, testing whether LH-induced resumption of meiosis is mediated through EGF signal transduction, EGFR kinase inhibitor AG1478 was added to LH-stimulated rat follicles. AG1478 blocked the LH-induced oocyte maturation as compared with control follicles (Tsafriri et al., 2005). In view of these data, it is hypothesized that Ar and Ep may act downstream of LH in an indirect, paracrine, cumulus-dependent manner.
LH-induced Ar and Ep biosynthesis signal pathway
It is well established that LH, secreted from the pituitary gland, initiates ovulation by binding to a specific G-protein-coupled receptor (GPCR), thus activating a hormone-sensitive adenylyl cyclase (Furman et al., 1986; Aharoni et al., 1993; Selvaraj and Amsterdam, 1997). The accumulated c-AMP, which acts as a second messenger, stimulates both resumption of meiosis and steroidogenesis (Seger et al., 2001) by the activation of protein kinase A (Salvador et al., 2002), steroidogenic proteins, enzymes like steroidogenic acute regulatory protein and cytochrome P450 side-chain cleavage enzyme system (reviewed in Omura and Morohashi, 1995). Although c-AMP is known to serve as a second messenger in isolated follicles or isolated COC, as well as in primary granulosa cell culture (Knecht et al., 1981; Rennert et al., 1991; Thomas et al., 2004), downstream events that lead to the biosynthesis of Ar and Ep are only partially clear. Recently, it was demonstrated that LH-induced biosynthesis of Ar and Ep in primary human granulosa cells is mediated at least in part by the c-AMP/protein kinase A (PKA) cascade (Freimann et al., 2004, 2005).
Ar and Ep are synthesized as integral membrane precursors with a single transmembrane domain (reviewed in Yarden and Sliwkowski, 2001). To gain biological activity, they must undergo a specific proteolytic cleavage of the ectodomain at the membrane surface by members of A Disintegrin And Metalloproteinases (ADAMs) (Dong et al., 1999; Hinkle et al., 2004). Interestingly, this shedding process was found to be regulated by GPCR signalling. GPCR agonists, such as lysophosphatidic acid and carbachol, stimulated the proteolytic cleavage and release of Ar in squamous cell carcinoma cells (Prenzel et al., 1999) Because the phorbol ester PMA was found to rapidly stimulate the shedding of heparin-binding EGF-like growth factor via the MAPK cascade (Gechtman et al., 1999), it has been proposed that GPCR-mediated activation of EGF-like factor cleavage is a mechanism of the GPCR signal transduction pathway (reviewed in Fischer et al., 2003). Recently, it was demonstrated that a wide range inhibitor of ADAMs reduces the activation of EGF receptor in rat follicles, thus interfering with the ovulation process (Ashkenazi et al., 2005).
A large number of proteinases have been implicated to have a role in the ovulation process. Metalloproteinases (MMPs), belonging to the metzincin family such as MMP-23 and MMP-14, were detected in granulosa cells (Liu et al., 1999; Ohnishi et al., 2001). Although MMP-14 was shown to be constitutively expressed (Liu et al., 1999), MMP-23 was down-regulated following gonadotrophin stimulation with FSH being more potent than LH (Ohnishi et al., 2001). These MMPs have strong collagenolytic activity and may be involved in follicular wall rupture upon LH stimulation (reviewed in Curry and Osteen, 2003). Our data from DNA microarray studies showed that stimulation of human granulosa cells with LH did not change most of the detectable MMPs such as MMP-1, MMP-2, MMP-9, MMP-12 and MMP-14. Our data also show that members of disintegrin and MMPs sub-family such as ADAM-9, ADAM-19, ADAM-21 and ADAM-23 were not changed by LH stimulation (unpublished data).
A family of secreted-type proteinases with thrombospondin motifs (ADAMTS) is able to cleave proteins as well as to separate their matrix-binding domains (Camaioni et al., 1996; Russell et al., 2003). ADAMTS-1, which is the most studied member of ADAMTSs in the ovary, was shown to be induced selectively by LH in granulosa cells and cumulus cells of pre-ovulatory follicles of mice (Robker et al., 2000) and rats (Espey et al., 2000). It is dependent on progesterone synthesis and expression of the progesterone receptor in granulosa cells (Robker et al., 2000). Recently, it has been suggested that ADAMTS-1 is involved in matrix organization during COC expansion in mice through cleavage of versican proteoglycan residing in the basal lamina (Russell et al., 2003). Likewise, in porcine COC, down-regulation of ADAMTS1 was associated with impairment of cumulus expansion (Shimada et al., 2004). Finally, although ADAM17/tumour necrosis factor--converting enzyme (TACE) was found to be involved in Ar cleavage in head and neck carcinoma cells (Gschwind et al., 2003), Ep shedding was found to be TACE-independent in various cells (Le Gall et al., 2003). Therefore, which of the ADAMs family member is involved in Ar and Ep processing in human ovary is yet to be determined.
Ar and Ep involvement in carcinogenesis
Ar and Ep, being EGF-like family members, confer binding specificity for the ErbB receptors (Yarden and Sliwkowski, 2001; Holbro and Hynes, 2004). Ar and its receptor, EGFR, were expressed in a series of invasive ductal breast carcinoma specimen (Ma et al., 2001). Ep was found to be involved in the stimulation of tyrosine phosphorylation of ErbB-4 and EGFR in human breast carcinoma cell lines (Komurasaki et al., 1997). Ep exerts a mitotic activity in various primary cell types such as rat hepatocytes (Toyoda et al., 1995), as well as in various types of human cancer cell lines, especially in epithelial tumour cell lines (Toyoda et al., 1997). Recently, an association of Ep expression in tumorigenesis through activated Ki-RAS-signalling pathway was suggested in human colon cancer cells (Baba et al., 2000). Likewise, Ep was found to be up-regulated and stimulated growth of human pancreatic cancer cells (Zhu et al., 2000). Furthermore, it was demonstrated that Ar might be involved in the pathogenesis and outcome of human ovarian cancer (D’Antonio et al., 2002).
Once Ep and Ar, which are known to be mitogenic, are generated and secreted from the granulosa cells, they might exert their effect not only on the cumulus cells as paracrine factors but also on the same membrana granulosa cells that produce them in an autocrine loop. Because Ar and Ep are preferentially paracrine, cumulus-dependent mediators (see Ar and Ep as LH mediators), it was hypothesized that following LH surge, down-regulation mechanism exists, which attenuates the autocrine loop, thus preventing these growth factors, potential to act as mitogens on the granulosa cells themselves (Freimann et al., 2004). Indeed, our data from DNA microarray studies showed a significant reduction in gene activity of ADAMTS1 and ADAM12 following LH stimulation (Table I). Furthermore, although there was no significant change in either ErbB-4 or EGFR expression, a significant down-regulation of EGF receptor substrate 8 (EPS8), which is essential for the mitogenic signals from the phosphorylated EGFR (Offenhauser et al., 2004; Leu et al., 2004), was demonstrated (Figure 2). Finally, based on RT–PCR technique, our recent data confirmed that ADAMTS1 and ADAM12 mRNA levels are down-regulated following LH stimulation of primary human granulosa cells (Freimann et al., 2005). Interestingly, in contrast to this down-regulation, which was concomitant with up-regulation of Ep and Ar expression, no change in ADAMTS1 and ADAM12 mRNA levels was observed in SV40-transformed human granulosa cells (Figure 3). These data suggest that loss of this down-regulation may be involved in the development of ovarian tumours.
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Conclusion |
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TopAbstractIntroductionInsulin-like growth factorsTransforming growth factorsVascular endothelial growth...Connective tissue growth factorEGF-like growth factorsConclusionReferences |
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Ovarian growth factors were traditionally considered to fulfil two major functions, namely supporting follicular growth and vascularization of the newly formed corpus luteum. However, DNA microarray technique, which revealed for the first time a dramatic up-regulation of the EGF-like factor gene transcripts, Ar and Ep, in human granulosa cell cultures in response to LH stimulation, has enlightened the enigmatic LH-mimicking effects of EGF on human COCs. These data served as a basis for the recent studies that demonstrated for the first time that these EGF-like growth factors play a crucial role in the induction of cumulus expansion and oocyte maturation in mice. Elucidating the molecular mechanism of the effect of these growth factors on the COC is one of the most important challenges for future research to come. Using DNA microarray technique, which may reveal the repertoire of genes activated in cumulus cells in response to Ar and Ep stimulation, could assist in resolving this enigma.
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Acknowledgements |
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This study was supported by Yad-Avraham Center for Cancer Research, by a research grant from Mr Edgar L. Cadden and La Fundation Raphael et Regina Levy and by the Women Health Research Center at the Weizmann Institute of Science, Rehovot, Israel. A. Amsterdam is the incumbent of the Joyce and Ben B. Eisenberg, Professorial Chair in Molecular Endocrinology and Cancer Research at the Weizmann Institute of Science.
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