Human Reproduction Update Advance Access originally published online on October 27, 2006
Human Reproduction Update 2007 13(2):143-162; doi:10.1093/humupd/dml002
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Endocrine signaling in ovarian surface epithelium and cancer
Department of Obstetrics and Gynecology, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5. E-mail: peleung{at}interchange.ubc.ca
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Abstract |
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 TOP Abstract IntroductionPeptide hormones in OSE...Steroid hormones in OSE...Concluding remarksReferences |
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Ovarian cancer is the sixth most common cancer and the fifth leading cause of cancer-related death among women in developed countries. Greater than 85% of human ovarian cancer arises within the ovarian surface epithelium (OSE), with the remainder derived from granulosa cells or, rarely, stroma or germ cells. The pathophysiology of ovarian cancer is the least understood among all major human malignancies because of a poor understanding of the aetiological factors and mechanisms of ovarian cancer progression. There is increasing evidence suggesting that several key reproductive hormones, such as GnRH, gonadotrophins and sex steroids, regulate the growth of normal OSE and ovarian cancer cells. The objective of this review was to highlight the effects of these endocrine factors on ovarian cancer cell growth and to summarize the signalling mechanisms involved in normal human OSE and its neoplastic counterparts.
Key words: GnRH / gonadotrophin / hormonal carcinogenesis and signalling pathway / ovarian cancer / ovarian surface epithelium / steroid
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Introduction |
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TOPAbstractIntroductionPeptide hormones in OSE...Steroid hormones in OSE...Concluding remarksReferences |
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Ovarian cancer and ovarian surface epithelium
Although relatively uncommon compared with other cancers affecting women, ovarian cancer is the most lethal form of gynaecological cancer. For instance, while about 23 000 new cases were diagnosed in the United States in 2002, approximately 14 000 women died from the disorder in the same year (Jemal et al., 2002
). Overall, it is the sixth most common cancer and the fifth leading cause of cancer-related death among women in developed countries (Greenlee et al., 2000). With no proven method for early detection, only about one-quarter of women have localized disease at the time of diagnosis, resulting in poor 5-year survival rates (30–40%), regardless of therapy (Greenlee et al., 2000). To complicate matters, the aetiology of ovarian cancer remains poorly understood. Although recent studies have linked tobacco products/smoking to an increased incidence of a certain type of ovarian cancer (Marchbanks et al., 2000; Green et al., 2001; Modugno et al., 2002), epidemiological studies have, to date, failed to yield a consensus regarding the contribution of chemical carcinogens to the development of ovarian cancer. However, several lines of evidence suggest that a family history of ovarian cancer, particularly in first-degree relatives and carriers of BRCA1 or BRCA2 gene mutations (Gayther et al., 1996; Xu and Solomon, 1996; Auersperg et al., 2001), is a significant risk factor. Frequent ovulations, which repeatedly induce the rupture and repair of the ovarian surface epithelium (OSE), lead to an increased opportunity for genetic abnormality and represent another major risk factor. Early menarche, late menopause and nulliparity, all of which have more ovulation episodes, increase the risk of developing ovarian cancer. On the other hand, conditions in which ovulation is suppressed, such as multiple pregnancies and prolonged breastfeeding, have been reported to lower the risk of developing ovarian cancer (Ford et al., 1994, 1998; Greenlee et al., 2000).
Approximately 90% of human ovarian cancer arises within the OSE, with the rest originating from granulosa cells or, rarely, stroma or germ cells (Auersperg et al., 2001). The OSE is composed of a single layer of flat-to-cuboidal epithelial cells with few distinguishing features. Until recently, an appropriate animal model developing ovarian epithelial carcinoma did not exist, and methods to isolate and maintain the human OSE under experimental conditions have only been established in the past few years. Thus, in contrast to neoplasms in other organs, where the normal tissue of origin is well defined, the physiology and susceptibility of the OSE to oncogenic influences is not well understood (Auersperg et al., 2002; Wong and Auersperg, 2002).
Oncogenic signalling pathways in ovarian cancer
Several recent studies have contributed to our understanding of the biology of the OSE and ovarian carcinogenesis. During neoplastic progression, the tendency of the OSE to undergo epithelio-mesenchymal conversion diminishes, and the cells become increasingly committed to complex epithelial phenotypes, which include the appearance of E-cadherin (Sundfeldt et al., 1997; Kantak and Kramer, 1998), the receptor for hepatocyte growth factor (c-met) (Huntsman et al., 1999) and other secretory products such as mucins (Young et al., 1988; Van Niekerk et al., 1993). Tumourigenesis is thought to result, at least in part, from genetic abnormalities that lead to the disruption or enhancement of intracellular signalling pathways that control cell proliferation, apoptosis or metastasis. In recent years, several key signalling pathways have been extensively studied in ovarian cancer cells, including the loss of tumour-suppressor genes, failure of cell-cycle regulation, up-regulation of telomerase and activation of oncogenic pathways. Specifically, tumoursuppressor genes such as BRCA1/BRCA2 (Greenlee et al., 2000), p53 (Kacinski et al., 1989), PTEN (Kurose et al., 2001), Lot-1 (Abdollahi et al., 1997), OVCA-1 (Schultz et al., 1996), DOC-2 (Mok et al., 1996) and NOEY2 (ARHI) (Yu et al., 1999) are highly mutated in ovarian cancer. While the interaction of cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) is tightly regulated in normal cells, some ovarian cancer cells lose their growth regulation as a result of the overexpression of cyclins/CDKs and/or the loss of CDKIs such as p21 and p27 (Garzetti et al., 1995; Ichikawa et al., 1996; Worsley et al., 1997; Anttila et al., 1999; Schmider et al., 2000; Farley et al., 2003). Ovarian cancer cells have high levels of telomerase, a ribonucleoprotein enzyme complex that adds new oligonucleotide repeats to the ends of chromosomes, which maintains telomere length and eventually results in rescue from senescence and resistance to apoptosis (Counter et al., 1994; Kim et al., 1994; Kyo et al., 1996). In contrast, normal OSE and pre-malignant lesions have little or no telomerase activity (Counter et al., 1994; Kruk et al., 1999). Oncogenic signalling molecules, such as phosphoinositide 3-kinase (PI3K)/Akt (Cheng et al., 1992; Mills et al., 2001), k-Ras (Enomoto et al., 1991), Src (Wiener et al., 2003), MAPK (Wang et al., 1999; Yazlovitskaya et al., 1999; Wong et al., 2001; Pan et al., 2002; Yamada et al., 2002) and STATs (Burke et al., 2001), and tyrosine kinase receptors, including ERBB2 (Berchuck et al., 1990), epidermal growth factor receptor (EGFR) (Kohler et al., 1989) and cFMS (the receptor for colony-stimulating factor I) (Kacinski et al., 1990), are frequently amplified in ovarian carcinomas. In addition, growth factors, hormones and even fluctuations in intracellular calcium levels can modulate cell proliferation and/or metastasis through the PI3K/Akt and MAPK pathways.
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases that are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus (Davis, 1994; Cobb and Goldsmith, 1995). MAPKs are divided into three major subgroups—ERK1/2, JNK and p38—of which ERK1 (p44 MAPK) and ERK2 (p42 MAPK) have been the most extensively studied. It is well established that the MAPK cascades are activated by two distinct classes of cell-surface receptors—receptor tyrosine kinases (RTKs) and G protein-coupled receptors (Crespo et al., 1994; Kasuya et al., 1994; Ohmichi et al., 1994; Cobb and Goldsmith, 1995; van Biesen et al., 1996). The intracellular signals arising from these cascades invariably lead to the activation of a set of molecules that regulate cell growth, division and/or differentiation. In ovarian cancer cells, MAPKs are regulated by cisplatin (Persons et al., 1999), paclitaxel (Wang et al., 1999), endothelin-1 (Vacca et al., 2000), GnRH (Kimura et al., 1999) and gonadotrophins (Choi et al., 2002, 2005).
PI3K is a heterodimer composed of a p85 (regulatory) and a p110 (catalytic) subunit. PI3K phosphorylates inositol lipids at the 3' position of the inositol ring to generate PtdIns-3-P, PtdIns-3,4-P2 and PtdIns-3,4,5-P3. Akt, also known as protein kinase B, is the best-characterized target of PtdIns-3,4-P2 and PtdIns-3,4,5-P3 (Datta et al., 1999; Kandel and Hay, 1999; Rameh and Cantley, 1999). The PI3K/Akt signalling pathway is now accepted as being at least as important as the ras-MAPK pathway in cell survival and proliferation, and hence its potential role in carcinogenesis is of immense interest. In ovarian cancer, it is becoming increasingly clear that the PI3K signalling pathway plays a major role in the regulation of cell proliferation, apoptosis, differentiation, tumourigenesis and angiogenesis (Chang et al., 2003; Brader and Eccles, 2004; Vara et al., 2004). PI3K is stimulated by estrogen, gonadotrophins, 4-hydroxy estradiol, hypoxia and lysophosphatidic acid in ovarian cancer cells (Lu et al., 2002; Gao et al., 2004; Vara et al., 2004; Xu et al., 2004; Choi et al., 2005). In addition, PI3K may be involved in cell migration, invasion and metastasis in normal and neoplastic tissues (Park et al., 2001; Tanno et al., 2001).
There is a growing body of evidence indicating that several key reproductive hormones can influence the incidence and/or growth characteristics of ovarian cancer (Cramer and Welch, 1983; Rao and Slotman, 1991; Hamilton, 1992; Godwin et al., 1993; Risch et al., 1994; Riman et al., 1998; Risch, 1998; Brekelmans, 2003). These findings are in line with the hormonal carcinogenesis hypothesis, suggesting that the endocrine factors that control the normal growth of target organs can also provide suitable conditions for neoplasmic transformation. Carcinomas of endocrine target tissues such as breast, uterus and ovary account for approximately 30% of cancer mortality in women. Unlike external risk factors such as diet and smoking, endogenous hormone levels are not easily modified, and thus it is important to understand the molecular changes induced by endocrine factors that might have a positive or negative association with neoplastic transformation in ovarian cancer. Here, we summarize recent data in support of a potential role for key reproductive hormones including peptide and steroid hormones, and their signalling mechanisms, in the control of normal and neoplastic OSE cell growth (Table I).
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Peptide hormones in OSE and ovarian cancer |
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The receptors for gonadotrophins and GnRHs belong to the G protein-coupled receptor (GPCR) superfamily. GPCRs are characterized by the presence of seven
-helical transmembrane domains and owe their name to their communication with GTP-binding proteins (G proteins), heterotrimeric proteins composed of -, ß- and 
-subunits. Receptor activation induces a conformational change in the G protein that triggers the exchange of GDP, bound to the -subunit, for GTP resulting in the activation and dissociation of G-subunits from Gß-subunits. Subsequently, the G- and Gß-subunits stimulate effector molecules such as adenylyl and guanylyl cyclases, phosphodiesterases, phospholipase C and PI3Ks, thereby activating or inhibiting the production of a variety of second messengers, including cAMP, cGMP, diacylglycerol and inositol trisphosphate. In addition, the induction of a calcium influx and the opening or closing of diverse ion channels are also associated with GPCR signalling. It is becoming increasingly clear that the regulation of proliferation and differentiation, in various normal or malignant cells, by GPCRs involves more multifaceted signalling mechanisms than has been previously documented. For example, GPCRs can modulate cellular processes independently of G proteins and/or can stimulate more than one subfamily of heterotrimeric G proteins in parallel (Gudermann et al., 1996; Hall et al., 1999; Brzostowski and Kimmel, 2001). Activin and inhibin belong to the transforming growth factor beta (TGF-ß) superfamily. Unlike gonadotrophins and GnRH, TGF-ß family members generally exert their actions through heteromeric complexes of type I and type II serine/threonine kinase receptors. Upon ligand binding to the type II receptor with constitutively active kinase, the type I receptor is recruited and phosphorylated and activated by type II receptor kinase. This activated receptor directly phosphorylates Smad proteins, intracellular mediators of the TGF-ß family in cytoplasm. To date, eight Smads have been identified in vertebrates, and they are classified into three subfamilies based on their structural and functional characteristics: receptor-regulated Smad (Smad 1, 2, 3, 5 and 8), common Smad (Smad 4) and inhibitory Smads (Smad 6 and 7). The receptor-regulated Smads are phosphorylated by type I receptor, which then form a complex with common Smad 4, and the complex moves into the nucleus to bind other transcription factors and/or specific DNA sequences in target promoters. Inhibitory Smads exert their role by blocking the interaction between receptor-related Smads and receptor. Finally, Smad signalling can be terminated through the proteolytic degradation of Smads via the ubiquitin-dependent pathway.
The hypothalamic decapeptide GnRH is a key neuroendocrine regulator in the mammalian reproductive system. It is released in a pulsatile manner from hypothalamic GnRH neurons and regulates the biosynthesis and secretion of gonadotrophins from pituitary gonadotropes. To date, 12 isoforms of GnRH have been identified in vertebrates. In addition to the classical mammalian GnRH (now referred to as GnRH-I), a second form of GnRH (GnRH-II) that is identical to chicken GnRH-II is expressed in humans (Lescheid et al., 1997; White et al., 1998). Besides the well-established function of GnRH-I in the control of gonadotrophin secretion from the pituitary, both GnRH-I and GnRH-II, presumably acting via a common receptor (GnRHR), have been shown to exert autocrine and/or paracrine effects in extrapituitary tissues including the ovary (Dong et al., 1993; Kang et al., 2001b). For instance, the expression of GnRH-I, GnRH-II and GnRHR has been demonstrated in different components of the human ovary, including granulosa-luteal cells, normal OSE cells, immortalized OSE (IOSE) cells and ovarian cancer cells (Peng et al., 1994; Kang et al., 2000b).
GnRH-I and its receptor (i.e. type I GnRH receptor; GnRHR-I) are expressed in 80% of human ovarian epithelial tumours, OSE cells and ovarian cancer cell lines (Emons et al., 1993; Miyazaki et al., 1997), suggesting that this decapeptide hormone may be an autocrine and/or paracrine regulator of the OSE and play a role in the pathophysiology of ovarian cancer (Savino et al., 1992; Schally, 1999; Schally et al., 2001; Grundker and Emons, 2003; Kang et al., 2003). Native GnRH-I and its synthetic analogues inhibit the growth of numerous GnRH receptor-bearing ovarian cancer cell lines in vitro (Lee et al., 1991; Emons et al., 1993; Peterson et al., 1994; Imai et al., 1996a; Kimura et al., 1999). It is of interest that antagonistic analogues of GnRH, such as Cetrorelix, may also exert dose-dependent anti-proliferative effects in ovarian cancer cells (Yano et al., 1994; Tang et al., 2002). The growth-inhibitory effects of GnRH analogues have also been observed in normal OSE cells (Kang et al., 2000a). More recently, it has been established that GnRH-II can induce growth inhibition in IOSE cells and ovarian cancer cells (Choi et al., 2001a; Grundker et al., 2002; Kang et al., 2003; Kim et al., 2004, 2005). Several reports have shown that GnRH analogues can induce apoptosis or regulate drug-induced apoptosis in ovarian cancers (Imai et al., 1998b; Motomura, 1998; Ohta et al., 1998; Grundker et al., 2000a; Gunthert et al., 2004). In nude mice, the suppression of endogenous gonadotrophin secretion from the pituitary by GnRH agonist (GnRHa) resulted in a growth inhibition of heterotransplanted ovarian cancers (Peterson et al., 1994). In one clinical study, GnRHa in combination with cytotoxic chemotherapy was therapeutically more useful than chemotherapy alone; however, other studies have found no relevant beneficial effects (Medl et al., 1993; Emons et al., 1996; Falkson et al., 1996).
GnRH-I binds to a specific receptor (GnRHR-I) that is a member of the rhodopsin-like GPCR family (Sealfon et al., 1997). GnRH–GnRHR signalling at the level of the pituitary has been extensively studied by many groups. In gonadotrope cells, GnRHR-I is coupled primarily to Gq and/or G11, and ligand binding results in the activation of phospholipase C, the production of diacylglycerol and inositol trisphosphate and the activation of protein kinase C (PKC) (Naor, 1990; Shah and Milligan, 1994; Harris et al., 1997; Shacham et al., 1999; Kraus et al., 2001). Furthermore, it appears that GnRH-I stimulates MAPK signalling pathways (including ERK, JNK and p38) primarily through a PKC-dependent pathway, thereby regulating gonadotrophin transcription (Naor et al., 2000; Kraus et al., 2001). Interestingly, the signalling pathways activated in response to GnRH–GnRHR association in nonpituitary cells appear to differ from those in pituitary cells (Kraus et al., 2001). For instance, the anti-proliferative effects of GnRH-I in ovarian cancer cells are mediated by coupling of GnRHR to Gi (Imai et al., 1996a,b; Grundker et al., 2000b), as with prostate cancer cells (Limonta et al., 1999), but not Gq, while one report suggests the involvement of Gß (Kimura et al., 1999).
Although MAPKs are regulated by GnRH-I in both normal and malignant OSE cells, the up- and downstream mechanisms seem to vary from cell to cell. Data from our laboratory have shown that GnRH-Ia induce a biphasic pattern of ERK phosphorylation in OVCAR-3 cells, such that a lower dose (10–10M) decreased ERK activity, while higher doses (10–7 and 10–6M) stimulated the activation of ERK (Kang et al., 2000c). In CaOV-3 cells, the activation of MAPK by a high dose of GnRHa (10–6M) leads to growth inhibition. The activation of ERK is mediated by dissociated Gß dimer and subsequent activation of son of sevenless, leading to the phosphorylation of Shc and MEK in a PKC- and extracellular calcium-independent manner. Subsequently, active ERK induces the dephosphorylation of the retinoblastoma protein, resulting in the inhibition of cell-cycle progression from G1 to S phase (Kimura et al., 1999).
Reversible protein phosphorylations catalysed by kinases and phosphatases play a key role in many cellular functions including proliferation. Several lines of evidence suggest that GnRHa regulates cell growth by activating a phosphotyrosine phosphatase (PTP) that mediates the dephosphorylation of membrane protein substrates in ovarian cancer cells (Imai et al., 1996a; Grundker et al., 2001). More recently, it has been reported that GnRH-I can modulate the activity of serine/threonine protein phosphatases and MAPK signalling in ovarian cancer (Sugiyama et al., 2003). Emons and colleagues demonstrated that GnRH-I activated PTP, via coupling of GnRHR to Gi, and reverse EGF-induced phosphorylation of the EGF receptor in ovarian cancer cells. These effects were PKC independent and involved in a significant inhibition of growth factor-induced ERK1/2 activation, c-fos expression and, eventually, cell proliferation (Lee et al., 1991; Imai et al., 1996a). Of note is their suggestion that GnRHa utilizes different signalling mechanisms to exert two opposite effects in ovarian cancer cells, namely, a growth-inhibitory effect, as mentioned above (Lee et al., 1991; Imai et al., 1996a), and an anti-apoptotic effect mediated by the NF
ß pathway (Grundker et al., 2000a), wherein GnRHa inhibits DNA-replication-dependent-cytotoxic agent and UV-light-induced apoptosis, but not CD95-mediated apoptosis (Grundker et al., 2000a; Gunthert et al., 2004). In contrast to these findings, two reports have suggested that the growth-inhibitory action of GnRH analogues in ovarian cancer might also be mediated by the stimulation of apoptotic cell death. Indeed, treatment of ovarian cancer cells with GnRHa induces a dose-dependent up-regulation of the proapoptotic factor Fas ligand (Imai et al., 1997), the receptor of which is frequently expressed in GnRHR-bearing ovarian tumours (Imai et al., 1998a). In addition, Tang et al. (2002) used flow cytometry and Tunnel staining to demonstrate the induction of apoptosis by Cetrorelix in HTOA cells. Furthermore, GnRHa increased the cisplatin sensitivity of ovarian cancer by reducing telomerase activity without changing its mRNA level (Ohta et al., 1998). Lastly, additional mechanisms have been suggested to account for the anti-proliferative effects of GnRHa in ovarian cancer, including the stimulation of JunD-DNA binding (Gunthert et al., 2002) and the inhibition of estradiol (E2)-induced serum response element (SRE) activity (Grundker et al., 2004). It is clear that additional research is needed to complete our understanding of the role of GnRH in the regulation of proliferation and apoptosis.
Some studies have reported that certain GnRH-I antagonists may behave like GnRHa to induce growth inhibition of ovarian cancers. Indeed Cetrorelix, a GnRH-I antagonist, appears to regulate several steps in cell-cycle progression including G1 phase cell-cycle arrest coupled with down-regulation of cyclin A-CDK2 complex levels, up-regulation of p53 and p21 protein levels and apoptosis (Tang et al., 2002). Given that certain GnRH-I antagonists can exert agonistic effects on the marmoset GnRH type II receptor (GnRHR-II), GnRHR-II has been regarded as the potential target of GnRH-I antagonists (Cheng and Leung, 2005). However, it has also been demonstrated that GnRHR-I mediates the agonistic activity of a GnRH-I antagonist in tumour cells such as JEG-3, BPH-1 and HEK293. As such, the mechanism of GnRH antagonist-induced agonistic activities in ovarian cancer remains elusive (Maudsley et al., 2004).
We and others have shown that, like GnRH-I, GnRH-II exerts anti-proliferative effects in normal and neoplastic OSE cells (Choi et al., 2001a; Grundker et al., 2002; Kim et al., 2004, 2005). Despite the presence of two types of GnRH-binding sites (Emons et al., 1993) and mRNA expression of GnRHR-II in ovarian cancer cells (Grundker et al., 2002), a functional full-length type II receptor has not been found in human tissues (Millar, 2003; Gault et al., 2004). Indeed, GnRH-II has been shown to bind to the type I GnRHR (Fromme et al., 2001; Sun et al., 2001; Pfleger et al., 2002), suggesting that the GnRH-I receptor may function as the cognate receptor for GnRH-II. At present, the molecular mechanisms underlying the various known effects of GnRH-II are not well understood. However, GnRH-II significantly activated ERK2 in COS7 cells expressing either human type I or marmoset type II receptor. In cells expressing the type I receptor, GnRH-II was less potent than GnRH-I in terms of ERK2 activation; however, significant activation of p38 was detected following the stimulation of the type II receptor with GnRH-II (Millar et al., 2001). In JEG-3 choriocarcinoma and benign prostate hyperplasia (BPH-1) cells, GnRH-II increased the phosphorylation of ERK1/2 at 10 min (Maudsley et al., 2004).
Recent findings from our laboratory have shown that p38 and ERK1/2, but not JNK, are involved in GnRH-II-induced anti-proliferation and/or apoptosis in ovarian cancer cells (Kim et al., 2004, 2005). Specifically, treatment with GnRH-II (100 nM) induced the activation of p38 MAPK and AP-1 (a transcription factor) that were significantly inhibited by pretreatment with a specific inhibitor of p38, SB203580 (Kim et al., 2004) (Figure 1). In addition, phosphorylation of ERK1/2 and Elk-1, but not JNK/SAPK, was observed following treatment with GnRH-II in OVCAR-3 cells. PD98059, a specific inhibitor of MAPK/ERK kinase, reversed GnRH-II-stimulated ERK1/2 activation (Kim et al., 2005). In terms of functional effects, treatment with GnRH-II gave rise to a reduction in DNA synthesis, a decrease in cell number and apoptosis, as determined by thymidine incorporation, the [(3)H]thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and DNA fragmentation assays. The ability of both SB203580 and PD98059 to block these effects suggests that GnRH-II-induced activation of p38 and ERK1/2 is functionally important.
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Gonadotrophins
The gonadotrophins, FSH and LH, are glycoprotein hormones synthesized in the anterior pituitary, which share similar chemical and structural features. Both hormones are key regulators of reproduction, acting in an endocrine manner to regulate steroidogenesis and gametogenesis in the ovary and testis. The FSH receptor (FSHR) is expressed by granulosa cells in developing ovarian follicles, while the LH receptor (LHR) is expressed by theca cells in early developing follicles and by both theca cells and granulosa cells during the later stages of follicular development. The actions of FSH and LH on granulosa and theca cells have been well characterized and are essential for follicular development (Rao et al., 1978; Richards and Farookhi, 1978); however, the roles of FSH and LH in OSE and ovarian epithelial cancer are not fully characterized.
Although the mechanisms involved in ovarian cancer tumourigenesis are not fully understood, one hypothesis currently being tested is that gonadotrophins may be involved in the transformation and progression of normal OSE to neoplastic OSE. Indeed, ovarian cancer is more common in conditions where gonadotrophin levels are elevated, such as in post-menopausal women or in women who have received treatment for the induction of ovulation (Rao and Slotman, 1991; Whittemore et al., 1992; Shoham, 1994; Balen, 1995). Reduced risk for ovarian cancer is associated with multiple pregnancies, breastfeeding, oral contraceptives and estrogen-replacement therapy, all of which are associated with lower levels of and/or reduced exposure to gonadotrophins (Stadel, 1975; Rao and Slotman, 1991; Rossing et al., 1994; Shoham, 1994). Moreover, levels of ovarian and peritoneal gonadotrophins appear to be elevated in ovarian cancer patients. For instance, LH levels in the peritoneal fluid and ovarian cyst fluid from tumour aspirates are significantly higher in patients with ovarian cancer or borderline ovarian tumour than in patients with benign cyst/tumours (Halperin et al., 2003; Chudecka-Glaz et al., 2004). The concentrations of both the gonadotrophins in the ovarian cancer fluid are greater than in borderline tumours, benign tumours and functional cysts of the ovary, and their serum/tumour ratio is lowest in ovarian cancer (Rzepka-Gorska et al., 2004).
FSHR and LHR expression has been demonstrated in normal OSE cells and ovarian tumours (Kobayashi et al., 1996; Mandai et al., 1997; Minegishi et al., 2000; Zheng et al., 2000; Parrott et al., 2001). Recent studies have suggested a relationship between the expression of gonadotrophin receptor and ovarian cancer development (Lu et al., 2000; Syed et al., 2001; Wang et al., 2003). Indeed, the relative mRNA levels of FSHR in ovarian cancer cells were higher than those in primary cultures of human OSE cells or in immortalized cell lines (Syed et al., 2001). Furthermore, FSHR levels increased from presumed precursor lesions (OEIs, ovarian epithelial inclusion) to benign OETs (ovarian epithelial tumour) and to borderline OETs, while its levels decreased from borderline OETs to ovarian carcinomas (Wang et al., 2003). These observations suggest that both serum FSH levels and FSHR levels in the ovarian epithelium may play a role in ovarian cancer tumourigenesis. In this regard, we sought to investigate the molecular events associated with FSHR expression in ovarian epithelial cells. In preneoplastic IOSE cells, the overexpression of FSHR activated ERK1/2 and increased the expression of EGFR, c-myc and HER-2/neu, all of which are generally overexpressed in ovarian cancer. In addition, the overexpression of FSHR accelerated cell proliferation, thus supporting a pivotal role for FSHR in ovarian cancer development, especially in terms of neoplastic conversion and growth potential (Choi et al., 2004).
Despite some controversial reports (Wimalasena et al., 1991; Venn et al., 1995; Ivarsson et al., 2001; Tourgeman et al., 2002), FSH and LH/HCG treatment appears to stimulate the growth of normal OSE, IOSE and some ovarian cancer cells in both a dose- and time-dependent manner in vitro (Wimalasena et al., 1992; Kurbacher et al., 1995; Kraemer et al., 2001; Ohtani et al., 2001; Parrott et al., 2001; Syed et al., 2001; Choi et al., 2002). In addition, gonadotrophins have been shown to enhance tumour angiogenesis and adhesion in ovarian cancer cells (Schiffenbauer et al., 2002; Wang et al., 2002; Zygmunt et al., 2002). Despite these observations, whether gonadotrophins play a role in normal OSE biology and ovarian tumourigenesis remains to be fully elucidated. Moreover, the exact mechanism of the response to gonadotrophins is not clearly understood. Recently, two cDNA microarray studies have examined the gene-expression profiles of normal and neoplastic cells following treatment with FSH (Ho et al., 2003; Ji et al., 2004). Although no matching genes were found between the two studies, FSH was shown to regulate a set of oncogenic and tumour-suppressor genes in both studies. For example, in MCV152 cells treated with FSH, most of the up-regulated genes were related to metabolism, increased cell proliferation and oncogenesis. In contrast, tumour-suppressor genes (RB1, BRCA1 and BS69) and genes related to decreased cell proliferation were down-regulated (Ji et al., 2004). There is also a report that gonadotrophins stimulate E2 secretion from granulosa cells and modulate steroid-dependent growth stimulation of OVCAR-3 cells (Kraemer et al., 2001). Moreover, recent studies have suggested interactions between gonadotrophins and growth factors or cytokines. For instance, combined treatments of HCG with estradiol may regulate the growth response of epithelial ovarian cancer cells through a mechanism involving insulin-like growth factor (IGF)-I (Wimalasena et al., 1993). In addition, FSH and HCG stimulated steady-state mRNA levels of keratinocyte growth factor, hepatocyte growth factor and kit ligand in bovine OSE cells (Shoham, 1994). Moreover, FSH-, LH- and estrogen-stimulated IOSE cell proliferation involves the interleukin-6 (IL-6)/signal transducer and activator of transcription-3 (STAT3) signalling pathway (Sundfeldt et al., 1997; Syed et al., 2002). At present, little information exists regarding the effect of gonadotrophins on metastasis-related functions; however, the in vivo growth of human ovarian carcinoma is promoted by elevated levels of gonadotrophins through increased tumour angiogenesis (Schiffenbauer et al., 1997; Zygmunt et al., 2002). In addition, the level of vascular endothelial growth factor is significantly elevated in both low malignant potential and serous ovarian carcinoma (Wang et al., 2002). Finally, treatment with gonadotrophin induced an increase in the expression of integrin subunit alpha(v) and CD44 (cell-surface hyaluronan receptor) in MLS human epithelial ovarian carcinoma cells (Schiffenbauer et al., 2002).
It is accepted that the effects of gonadotrophins on granulosa and Leydig cells are mediated by the protein kinase A (PKA) pathway, such that the activation of adenylyl cyclase by the stimulatory G protein, Gs, is followed by a rapid increase in cAMP and a subsequent activation of PKA (Hsueh et al., 1984). Some studies have proposed that the PKA pathway is also involved in gonadotrophin-induced proliferation of OSE and ovarian cancer cells. For instance, a specific PKA inhibitor, H89, completely abolished gonadotrophin-stimulated cell growth via the IL-6/STAT3 pathway in human OSE and ovarian cancer (Syed et al., 2001, 2002). Interestingly, there is increasing evidence that, in addition to cAMP/PKA, FSHR and LHR can activate a number of key cellular signalling pathways such as PKC, PI3K and MAPK in granulosa cells (Pennybacker and Herman, 1991; Flores et al., 1992; Cameron et al., 1996; Das et al., 1996; Herrlich et al., 1996; Chiang et al., 1997; Babu et al., 2000; Gonzalez-Robayna et al., 2000; Sekar and Veldhuis, 2001; Cunningham et al., 2003; Alam et al., 2004). In this regard, the use of alternative/additional signalling pathways by FSHR and LHR in OSE and ovarian cancer cells needs to be evaluated.
Initial attempts to explore this question have found that treatment of epithelial ovarian cancer cells with FSH significantly increased the levels of PKC mRNA and protein, suggesting that the stimulation of PKC transcription is involved in FSH-induced cell proliferation (Ohtani et al., 2001). Our findings have demonstrated that the phosphorylation of ERK1/2 and cell growth was significantly increased in preneoplastic IOSE-29 and neoplastic IOSE-29EC cells following treatment with FSH (Choi et al., 2001a). FSH-induced activation of ERK1/2 and proliferation were completely abolished in the presence of PD98059, suggesting that the growth-stimulatory effect of FSH is mediated by ERK. In addition, treatment with FSH significantly phosphorylated a transcription factor, Elk-1, which is a well-known downstream target of ERK1/2. It is of interest to note that FSH did not stimulate basal cAMP levels in OSE cells, while it did in human granulosa cells (Choi et al., 2002). More recently, we reported that gonadotrophins up-regulate EGFR levels through activation of ERK1/2 and PI3K in human IOSE cells (Choi et al., 2005). Treatment of IOSE-80PC cells with FSH and LH resulted in a significant increase in EGFR mRNA at 24 h and EGFR protein at 48 h, whereas only a mild increase was observed in OVCAR-3 cells. In addition, IOSE-80PC cells treated with gonadotrophins and EGF exhibited an additive stimulation of mitogenesis. FSH and LH significantly increased the activities of various kinases at 5–10 min, and pretreatments with LY294002 (an inhibitor of PI3K) or PD98059 partially blocked gonadotrophin-induced up-regulation of EGFR mRNA in IOSE-80PC cells (Figure 2). Interestingly, our results suggest that FSH and LH use different mechanisms to increase EGFR mRNA, such that the former increases EGFR gene transcription, while the latter enhances EGFR mRNA stability. Taken together, these results suggest that FSH- and LH-induced activation of the ERK and PI3K/Akt pathways may affect cell growth by means of a direct mitogenic effect or by interaction with a growth factor system, such as EGFR, in preneoplastic ovarian surface epithelial cells. To date, the signalling events occurring up- and downstream of ERK and PI3K/Akt activation by gonadotrophins in OSE and ovarian cancer are unknown. Recent findings have highlighted the potential importance of cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs or Epac; exchange protein directly activated by cAMP) (Altschuler et al., 1995; Gonzalez-Robayna et al., 2000) and APPL1 (adaptor protein containing PH domain, PTB domain and leucine zipper motif) (Nechamen et al., 2004) in gonadotrophin receptor signal transduction. cAMP-GEFs regulate small GTPases, such as Rap1, which can stimulate Raf or Ras kinase and lead to the activation of the PI3K/Akt and MAPK pathways (Kawasaki et al., 1998; de Rooij et al., 1998; Gille and Downward, 1999). In OVCAR-3 cells, activation of the Gs-coupled ß2-adrenergic receptor increased cAMP levels and stimulated integrin-mediated cell adhesion via Epac and Rap1 (Rangarajan et al., 2003). Furthermore, the identification of a binding partner for FSHR, APPL1, provides a potential link between GPCR activation and PI3K signalling. Specifically, APPL1 interacts with the p110 catalytic subunit of PI3K and with inactive Akt resulting in their activation (Mitsuuchi et al., 1999).
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Activin and inhibin
Activin and inhibin are members of the TGF-ß superfamily. They are structurally related glycoproteins, consisting of two subunits linked by disulphide bonds. Inhibin is composed of an -subunit and one of two ß-subunits forming -ßA (inhibin A) or -ßB (inhibin B), whereas activin is formed from a combination of two of the same or different ß-subunits, ßA-ßB (activin A), ßB-ßB (activin B) or ßA-ßB (activinAB). Four receptors are known to bind activin with high affinity (ActR-IA, ActR-IB, ActR-IIA and ActR-IIB), although these receptors can also bind to and mediate the actions of other ligands of the TGF-ß superfamily such as BMP (bone morphogenetic protein) (Harrison et al., 2004). To date, there is no known receptor that specifically binds inhibin with high affinity. Based on the recent evidence of inhibin-mediated antagonism of activin signalling, it is believed that inhibin exerts its role, at least in part, by neutralizing activin action in association with co-receptors such as betaglycan and p120 (Robertson et al., 2000; Farnworth et al., 2001).
In addition to the regulation of FSH secretion from the pituitary gonadotropes, these gonadal peptides are known to influence various ovarian functions such as oocyte maturation, steroid synthesis and proliferation in an autocrine and/or paracrine manner (Rabinovici et al., 1990; Findlay, 1994; Rainey et al., 1996; Silva et al., 1999). More recently, the involvement of the activin/inhibin system in various aspects of ovarian cancer pathophysiology including diagnosis, development and progression has been suggested. The diagnostic value of serum inhibin assay for women after menopause has been suggested in granulosa cell and mucinous-type ovarian epithelium tumours (Robertson et al., 2004). In a series of animal studies, it has been shown that inhibin -deficient mice model resulted in sex-cord stromal tumour without exception and elevated serum activin level (Matzuk et al., 1992, 1996; Coerver et al., 1996), suggesting the potential role of inhibin as a tumour-suppressor gene. OSE and/or its neoplastic counterparts have also shown the expression of the activin receptor and inhibin co-receptor as well as inhibin/activin subunit (Welt et al., 1997; Zheng et al., 1997, 1998; Ito et al., 2000; Minegishi et al., 2000; Choi et al., 2001b; Fuller et al., 2002; Steller et al., 2005), suggesting the possible autocrine/paracrine role of activin/inhibin in these cells. In situ hybridization and RT-PCR study showed activin/inhibin - and ß-subunit mRNA expression in four of seven primary OSE (Zheng et al., 1997). Studies on diverse histological type of primary epithelial cancer have suggested that malignant ovarian cancer shows decreased inhibin/activin ratio compared with normal OSE or nonmalignant tumour (Welt et al., 1997; Zheng et al., 1998; Yamashita et al., 1999). Accordingly, we found that mRNA of activin/inhibin - and ßA-subunits was highly expressed in normal OSE compared to OVCAR-3 cells. In contrast, ßB subunit and activin receptor IIA were significantly higher in OVCAR-3 cells compared to OSE cells (Choi et al., 2001b). Collectively, these findings suggest that differential expression of activin/inhibin subunits, resulting in an imbalance of activin/inhibin expression, in OSE may be a determinant of ovarian cancer development.
Activin has been thought to be a mitogenic factor in some ovarian cancer cell lines but not in normal OSE (Di Simone et al., 1996; Fukuda et al., 1998; Choi et al., 2001b; Steller et al., 2005). We demonstrated that treatment with activin significantly stimulates cell proliferation in a well-established ovarian cancer cell line, OVCAR-3, but not in normal OSE cells (Choi et al., 2001b). In contrast, preneoplastic IOSE cell, IOSE-29, showed decreased proliferation following treatment with activin (Choi et al., 2001d). These results suggest that activin may be involved in growth inhibition in early neoplastic stage but growth stimulation in late malignant stage of ovarian cancer. It is noteworthy that activin A increased invasiveness of ovarian cancer SKOV-3 and OCC1 cells as well as its proliferation (Steller et al., 2005). Relatively little is known about the potential role of inhibin A in ovarian cancer. Inhibin A decreased proliferation in normal OSE cells and three of eight ovarian cancer cell lines (SKOV-3, A2780-s and OVCAR-3 cells). Nude mice injected with inhibin-responsive SKOV-3 cells showed a longer life span compared with the inhibin-resistant OCC-1 cells, implicating the involvement of inhibin resistance with poor prognosis of ovarian cancer (Steller et al., 2005).
The mechanism by which activin/inhibin regulates proliferation and invasion in OSE and ovarian cancer is not known. Based on the studies in other cell systems, activin first binds to type II receptors, which then recruit and phosphorylate type I receptor ActR-IB primarily, but not exclusively, at the GS domain, followed by phosphorylation of Smad 2/3 and consequent formation of complex with Smad 4. While Smad 7 interferes with the communication between those receptor-related Smads and receptors, SARA (Smad anchor for receptor activation) and Hgs facilitate activin signalling by recruiting Smad 2/3 to activin receptors in the cytoplasm (Tsukazaki et al., 1998). In addition, activin signalling can be blocked at the receptor level by their binding proteins, follistatin, and by inhibin. In normal and malignant ovarian cells, we and other groups have demonstrated the expression of intracellular components of activin signalling pathway. The mRNA level of Smad-2 was increased after activin treatment, whereas no difference was observed in Smad-4 mRNA levels in OVCAR-3 cells (Ito et al., 2000). Levels of Smad 2, 3 and 4 between OSE and ovarian cancer were not different, while up-regulation of SARA, a facilitator of the activin signalling transduction pathway, was observed in SKOV-3 and OCC-1 ovarian cancer cells (Steller et al., 2005). Treatment with activin A for 1 h stimulated the phosphorylation of Smad-2/3 in CaOV-3 cells (Fu et al., 2003). Although TGF-ß family members have been shown to stimulate other signalling pathways including p38/MAPK in addition to the Smad pathway, alternative signalling has not been reported in activin signalling, to date (Hanafusa et al., 1999; Sano et al., 1999). As for inhibin signalling in OSE and ovarian cancer, betaglycan, the co-receptor of inhibin, was observed in OSE and ovarian cancer (Fuller et al., 2002; Steller et al., 2005). However, whether or not it blocks the binding of activin to its receptor in ovarian cancer cells, like in other cell systems (Robertson et al., 2000; Farnworth et al., 2001; Wiater and Vale, 2003), remains to be determined.
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Steroid hormones in OSE and ovarian cancer |
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TOPAbstractIntroductionPeptide hormones in OSE...Steroid hormones in OSE...Concluding remarksReferences |
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Sex steroid hormones have been implicated in the aetiology and/or progression of some epithelial ovarian cancers. Expression of estrogen (ER), progesterone (PR) and androgen (AR) receptors has been reported in human epithelial ovarian cancer (Hamilton et al., 1981
; Rao and Slotman, 1991; Chadha et al., 1993; Cardillo et al., 1998; Hillier et al., 1998; Pujol et al., 1998; Lau et al., 1999; Akahira et al., 2002). The effects of ovarian steroid hormones, including estrogen, progesterone and androgen, are primarily mediated through interaction with their receptors that belong to the nuclear receptor superfamily of transcription factors. Hormone binding leads to specific conformational changes followed by dissociation from heat-shock protein complexes, receptor dimerization and nuclear localization (Segnitz and Gehring, 1995). Dimerized receptors associate with hormone response elements (HRE), usually located within the promoter region of target genes, and recruit a complex of proteins which includes co-regulators. Interestingly, nuclear hormone receptors and their co-regulators can be phosphorylated, and there is ample evidence to suggest that phosphorylation can regulate the activation of steroid receptors in either a hormone-dependent or hormone-independent fashion. For example, a number of growth factors [IGF-I (Aronica and Katzenellenbogen, 1993), TGF- (Bunone et al., 1996) and heregulin (Pietras et al., 1995)] utilize multiple signal transduction pathways, including MAPK and PI3K/Akt, to activate ER and initiate estrogen response element (ERE)-mediated gene expression (Lee et al., 1997). Thus, an emerging concept in steroid receptor biology is that they function not only as direct transducers of hormonal effects but, as part of the nuclear transcription factor pool, also serve as key points of convergence for multiple signal transduction pathways (McDonnell et al., 1995). Furthermore, it has been demonstrated that steroids can induce the activation of various signalling pathways, although the exact mechanism is still controversial. For instance, steroid hormones acting through ER, PR and AR can activate ERK by interacting with and activating Src kinase, a tyrosine kinase (Falkenstein et al., 2000). Although the involvement and molecular mechanisms of steroids in the development of breast, endometrial and prostate cancers have been relatively well studied, there is paucity of information about steroid signalling in ovarian cancer.
Although the risk of ovarian cancer when undergoing hormonal replacement therapy is still controversial (Garg et al., 1998; Negri et al., 1999; Coughlin et al., 2000; Riman et al., 2002), recent prospective epidemiological studies on post-menopausal women have suggested that estrogen-only replacement therapy increases ovarian cancer incidence and mortality (Rodriguez et al., 2001; Lacey et al., 2002). There is evidence indicating that estrogens taken as oral contraceptives during premenopausal years are protective, whereas when used in post-menopausal years may increase the risk of ovarian cancer (Rao and Slotman, 1991; Garg et al., 1998; Risch, 1998). Physiologically, E2 and estrone (E1) are mainly produced by follicular granulosa cells. Post-menopausal women with ovarian epithelial cancer have increased levels of peripheral and ovarian venous sex steroids, including E1 and E2 (Heinonen et al., 1986), and there is evidence that E2 is produced in human epithelial ovarian cancer cells (Wimalasena et al., 1991; Taube et al., 2002). Furthermore, aromatase expression was found in OSE, epithelial ovarian tumours and in some ovarian cancer cell lines, including BG-1, PE04 and PE014 (Cunat et al., 2005). These findings suggest that estrogen may provide a hormonal environment that promotes tumour progression and/or may play an active role in regulating the proliferation/survival of these cells.
ERs are expressed in normal OSE cells as well as in ovarian cancers (Hillier et al., 1998; Pujol et al., 1998; Lau et al., 1999). Specifically, ER is expressed in up to 60% of ovarian epithelial tumours where its levels are generally higher than in benign tumours or normal ovaries (Vierikko et al., 1983; Willcocks et al., 1983; Rao and Slotman, 1991; Risch, 1998). In addition, the expression of ERß has been reported in normal OSE cells and in ovarian cancer cell lines at both the mRNA and protein levels by us (Choi et al., 2001c) and others (Brandenberger et al., 1998; Lau and Matzuk, 1999). However, a majority of studies suggest an increased ER:ERß ratio in ovarian cancer, implying a mechanism that results in ER overexpression or a selective growth advantage for ER-positive cells (Brandenberger et al., 1998; Pujol et al., 1998; Rutherford et al., 2000). SKOV-3 cells, which are insensitive to E2 with respect to cell proliferation and induction of gene expression, were found to possess a mutated ER resulting from a 32 bp deletion in exon 1 (Lau et al., 1999). This may provide an explanation for the lack of responsiveness and resistance to E2 in some ovarian cancers.
Treatment with exogenous estrogens stimulated the growth of several ER-positive ovarian carcinoma cell lines in vitro (Galtier-Dereure et al., 1992; Choi et al., 2001c). In addition to cell growth, estrogen may also affect ovarian cancer invasion (Song et al., 2005). Although the proliferative effects of estrogen on ovarian cancer have been relatively well characterized, its effects in normal OSE are still controversial. E2 seems to have a biphasic effect on the growth of normal OSE cells such that higher concentrations (µM) of estrogen inhibit cell growth (Keith Bechtel and Bonavida, 2001; Wright et al., 2002, 2003, 2005), whereas no response (Karlan et al., 1995; Bai et al., 2000; Choi et al., 2001c; Wright et al., 2002) or a proliferative response (Syed et al., 2001) is observed at lower concentrations (nM or pM). Using rhesus OSE cells, Wright et al. (2003, 2005) have demonstrated that micromolar doses of estrogen, similar to those observed during the time of ovulation in primates, inhibit phosphorylation of retinoblastoma, induce the expression of CDK inhibitors (p21 and p53) and result in cell-cycle arrest. In a neoplastic IOSE cell line, we have demonstrated that E2-mediated growth stimulation is attenuated by co-treatment with tamoxifen, an estrogen antagonist (Choi et al., 2001c). Moreover, the mechanism of E2 action may involve an up-regulation of bcl-2 (anti-apoptotic gene) at both the mRNA and protein levels (Choi et al., 2001c). Since no significant difference was observed in the mRNA and protein levels of bax (proapoptotic gene), our data suggest that estrogen may act by preventing apoptosis in tumorigenic OSE cells. Our observations are consistent with previous data suggesting that in SKOV-3 and OVCAR-3 cells E2 suppresses basal and cisplatin-induced apoptosis by increasing DNA repair capacity and avoiding apoptosis, eventually leading to uncontrolled cell growth and drug resistance of ovarian cancers in vivo (Murdoch and Van Kirk, 1997). In this regard, it is worth mentioning that BRCA1 (DNA repair gene) can be a ligand-reversible barrier to transcriptional activation by promoter-bound ER and that functional inactivation of this gene may promote tumourigenesis through inappropriate E2-mediated regulation of breast and ovarian epithelial cell proliferation (Zheng et al., 2001).
The mechanism of action of estrogen in ovarian cancer may be multifaceted. Classical estrogen signalling in ovarian cancer, via receptor binding in the nucleus, induces transcriptional activation of numerous genes. Some of them are key components of other hormonal systems, while others are regulators of the multistep carcinogenesis process that includes proliferation, motility and invasion (Chien et al., 1994; Hayashido et al., 1998; Rochefort et al., 2001; Yousef and Diamandis, 2002). Up-regulation of c-myc has been shown to mediate estrogen-induced ovarian cancer cell growth (Chien et al., 1994). Estrogen also regulates various genes involved in motility and invasion such as ezrin (Song et al., 2005), fibulin-1 (Galtier-Dereure et al., 1992; Clinton et al., 1996; Bardin et al., 2005), cathepsin D (Galtier-Dereure et al., 1992) and kallikreins (Yousef and Diamandis, 2002). In addition, estrogen may interact with other growth factors (EGF, TGF- and IGF-I) and cytokines (IL-6) in ovarian cancer cells. For example, an EGF receptor-targeted antibody attenuated the growth-stimulatory effects of estrogen in PE01 ovarian cancer cells (Simpson et al., 1998). Estrogen also induced a significant increase in TGF- concentration and altered EGF receptor expression in these cells. Estrogen potentiates EGFR- and IGFR-I-mediated cell growth by increasing receptor binding affinity and capacity, respectively (Wimalasena et al., 1993). In IOSE and ovarian cancer cells, estrogen increased IL-6 mRNA and protein expression, resulting in the activation of the STAT-3 signalling pathway. Last, treatment with E2 resulted in a decrease in IGF-binding protein-3 (IGFBP-3) and an increase in IGFBP-5 mRNA levels in ovarian cancer cells (Krywicki et al., 1993).
It is possible that the effect of E2 on ovarian cancer cell growth is mediated, in part, by its influence on other hormonal systems. Indeed, PR mRNA and protein expression was significantly down-regulated in human OSE and ovarian cancer cells following treatment with E2, thus explaining the antagonism of estrogens on the anti-ovarian cancer action of progestins (Mukherjee et al., 2005). The PR-B:PR-A mRNA ratio was augmented by E2 in a time- and dose-dependent manner in OVCAR-3 and CaOV-3 cells, but not in normal OSE cells (Akahira et al., 2002). PR-B protein levels were significantly increased in OVCAR-3 cells, whereas both PR-A and PR-B were increased in normal OSE cells, suggesting that down-regulation of PR-A may be involved in ovarian carcinogenesis (Akahira et al., 2002).
Interestingly, there appears to be a complex interaction between the E2 and GnRH systems in ovarian cancer. We have demonstrated that GnRH and GnRHR mRNAs are down-regulated by estrogen in OVCAR-3 cells (Kang et al., 2001a). Co-treatment with tamoxifen abolished the estrogen-mediated down-regulation of GnRH and GnRHR mRNA levels, suggesting a potential interaction between the E2/ER and GnRH/GnRHR systems in the regulation of growth in normal and neoplastic OSE cells (Kang et al., 2001a). Thus, the mechanism by which E2 contributes to ovarian carcinogenesis may, in part at least, be indirect and involve an attenuation of the anti-proliferative effect of GnRH. The molecular mechanism by which E2 exerts this inhibitory effect is unclear. In OVCAR-3 cells, we have shown that E2 could time- and dose-dependently suppress the activity of a 1.7 kb human GnRHR promoter-luciferase construct when ER- (but not ER-ß) was overexpressed. Using detailed 5'- and 3'-delection analysis, we have shown that the E2-response region was located between nucleotide –266 and –117 (relative to the translation start codon ATG), within which a putative ERE and an activating protein-1-binding site were identified (Cheng et al., 2003) (Figure 3). These observations suggest that E2-activated ER- represses the human GnRHR gene expression in ovarian tumours via an indirect mechanism involving CREB and possibly other transcriptional regulators.
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Since co-activators and co–repressors regulate the interaction of steroid hormone receptor complexes with transcriptional regulatory elements, their behaviour, with respect to cell- and tissue-specific hormonal responses, has been investigated in various hormone-sensitive systems. However, the importance and physiological roles of these factors in ovarian cancer have not yet been determined. Some studies have examined whether inappropriate expression of transcriptional co-regulators is related to the resistance of ovarian cancers to hormonal therapy (Eng et al., 1998
; Havrilesky et al., 2001). Specifically, the N-CoR and SMRT co-activators and the BRG-1 co-repressor were found to be expressed in ovarian cancer, but no correlation between their expression and hormone receptors was observed (Havrilesky et al., 2001). However, another co-activator, AIB1, is related to ER expression and poor prognosis in ovarian cancer (Tanner et al., 2000).
Tamoxifen, a potent estrogen antagonist, competitively binds to ER and is thought to exert its growth-inhibitory effects by blocking the proliferative effects of E2 (Jordan and Murphy, 1990). However, recent findings indicated that tamoxifen is effective in ER-negative breast and ovarian cancers as well as in ER-positive ones (Goldenberg and Froese, 1982; Taylor et al., 1984; Jaiyesimi et al., 1995; Markman et al., 1996). In ovarian cancer cells, the tamoxifen-inhibited cell growth appears to be ER independent because tamoxifen was effective in both ER-positive and ER-negative cells. In addition, low doses of tamoxifen induced cell-cycle arrest at the G1 phase via ERK signalling, while high doses induced apoptosis via the JNK and p38 pathways. Both effects were inhibited by -tocopherol, a lipid-soluble antioxidant, suggesting that oxidative stress is involved in the anti-proliferative effects of tamoxifen (Mabuchi et al., 2004).
Ligand-independent ER activation has been reported in ovarian cancers. For example, it has been suggested that CD44 membrane receptor signalling can induce the activation of ER. Indeed, CD44 interaction with hyaluronan, an important factor in the peritoneal spread of ovarian cancer, recruits IQGAP1, a binding partner for Rho GTPase, and induces the activation of ERK2. Activated ERK2 phosphorylates Elk-1 and Er, thus increasing Elk-1/ERE-mediated transcription and tumour migration via F-actin binding (Bourguignon et al., 2005). An interaction between EGF and ER signalling pathways has also been proposed in ovarian cancer. The anti-tumour drug, suramin, markedly induced the proliferation of ovarian cancer cells bearing both ER and EGFR, but inhibited the growth of cells expressing only EGFR. Interestingly, proliferative effects of suramin did not require the addition of estrogen and were not abolished by the pure estrogen antagonist, ICI 182,780, suggesting that activated ER is not a prerequisite.
Rapid nongenomic activation of multiple signal transduction pathways also appears to be critical for E2 action in ovarian cancer (Gao et al., 2004; Kimura et al., 2004). Treatment with E2 rapidly activates the PI3K/Akt pathway, resulting in the up-regulation of hTERT transcription, by both a fast NFß-dependent and a slow ERE-dependent mechanism, and post-transcriptional regulation. Moreover, E2-induced Akt phosphorylation was mediated by ER, Src and PI3K, suggesting that E2-ER may regulate the crosstalk between Src and PI3K (Kimura et al., 2004). Rapid activation of the PI3K/Akt pathway is also involved in the stimulation of hypoxia-inducible factor 1 and vascular endothelial growth factor A by 4-hydroxy E2 (Gao et al., 2004).
Conditions associated with high levels of progesterone (P4), such as multiparity and twin pregnancy, have been reported to reduce a woman’s risk of ovarian cancer (Adami et al., 1994; Thomas et al., 1998; Salazar-Martinez et al., 1999; Tambyraja et al., 2004), while women with progesterone deficiency were found to have a higher risk (Modan et al., 1998). Combined estrogen–progestin oral contraceptives have been associated with a reduced risk of ovarian cancer, with increasing duration of use, as little as 6 months in some studies, linked to greater risk reduction (Gross et al., 1992; Rosenberg et al., 1994; Ness et al., 2001; Greer et al., 2005). This protective effect against ovarian cancer is mainly due to the progestin component of oral contraceptives (Rodriguez et al., 1998). In this regard, numerous studies have examined the growth-inhibitory and/or apoptosis-inducing effects of P4 in an effort to test the hypothesis that it protects normal and malignant OSE from ovarian cancer development and progression. In vivo and in vitro studies have demonstrated that higher doses of progesterone, in the range observed during oral contraceptive use or perhaps during pregnancy, inhibit cell growth, induce apoptosis and/or inhibit invasion in monkey and human OSE and/or ovarian cancer cells (McDonnel and Murdoch, 2001; Wright et al., 2002).
Several lines of evidence indicated that the transcriptional activity of PRs can be modulated by variable expression of the A and B isoforms and through crosstalk with other signal transduction pathways. For instance, the PR-A:PR-B ratio in breast cancer is higher than in normal breast tissue, and patients with high PR-A levels have poorer disease-free survival rates (Hopp et al., 2004). Depending on the cell type and target promoter, PR-A can function as a transdominant repressor of other steroid hormone receptors including ER, AR, GR, MR and PR-B (Giangrande et al., 1997). Phosphorylation of PR by kinases, including CDK-2, MAPK and casein kinase II, and crosstalk with PKA, PKC and protein phosphatases 1 and 2A can modulate hormone-dependent PR transactivation in various cell lines treated with 8-bromo-cAMP, okadaic acid, EGF and 4ß-phorbol-12-myristate-13- acetate (PMA) (Weigel, 1996; Lange et al., 2000; Rowan et al., 2000; Knotts et al., 2001). Furthermore, PR can also induce rapid nongenomic effects by interacting directly with the SH3 domains of various cytoplasmic signal molecules. For example, rapid progestin-induced activation of Src and downstream MAPKs has been implicated in P4-induced growth inhibition of breast epithelial cells (Boonyaratanakornkit et al., 2001). However, the biology and molecular signalling mechanisms underlying the effects of progesterone in OSE and ovarian cancer are still largely unknown.
PR expression is considered to be a favourable prognostic marker in ovarian cancer (Lee et al., 2005). Interestingly, down-regulation of PR-A seems to be associated with the development of ovarian epithelial carcinoma, whereas the PR-A:PR-B ratio is increased during the development of breast cancer (Akahira et al., 2002). Using activating and blocking anti-FasL antibodies, Syed et al. have demonstrated that P4 induces apoptosis in both human OSE and ovarian cancer cells via regulation of the Fas/FasL-activated caspase-8 pathway. It is important to note that P4 increased the expression of FasL in human OSE cells, but decreased it in ovarian cancer cells, suggesting that the expression of co-regulators and/or transcriptional factors may change throughout neoplastic conversion (Syed et al., 2001; Syed and Ho, 2003). Recent cDNA microarray studies have revealed that P4 induces putative anti-tumorigenic genes including ATF-3, caveolin-1, DLC-1 and NM23-H2. The functions of these four genes are diverse—ATF-3 is an apoptosis inducer, NM23-H2 is a mobility suppressor and caveolin-1 and DLC-1 act like classical tumour suppressors (Syed et al., 2005). In monkey OSE cells, crosstalk between the progesterone and growth factor systems has been implicated in P4-induced apoptosis. Indeed, the differential regulation of TGF-ß1 (decreased) and TGF-ß2/3 (increased) was correlated with the apoptotic index of OSE cells from monkeys treated with progestin for 35 months (Rodriguez et al., 1998, 2002). In addition to the inhibition of cell growth, P4 plays a negative role in invasion of ovarian cancer cells. For example, invasion into Matrigel and secretion of uPA (urokinase plasminogen activator) were significantly reduced by progesterone in SKOV-3 cells. Inhibition of plasma membrane fluidity, which is essential for exocytosis of vesicles containing various factors including proteolytic enzymes, was associated with reduced secretion of uPA and subsequent loss of invasiveness (McDonnel and Murdoch, 2001; McDonnel et al., 2003). Interestingly, both RU486 (PR antagonist) and actinomycin D (transcriptional inhibitor) were unable to inhibit the suppression of uPA secretion by P4 during the first 6 h of treatment, suggesting the involvement of nongenomic mechanisms (McDonnel and Murdoch, 2001). Subsequent in vivo studies using athymic mice inoculated with SKOV-3 cells have shown that treatment with P4 reduces invasion into host tissues and embedding on intestines/mesentery, resulting in a prolonged life span (McDonnel et al., 2005).
AR is expressed in OSE cells and the majority of ovarian cancers (>90%) (Hamilton et al., 1981; Chadha et al., 1993; Cardillo et al., 1998). Women with polycystic ovary syndrome, a condition associated with anovulation and hyperandrogenaemia, have a higher risk of developing ovarian cancer (Schildkraut et al., 1996). Furthermore, the microenvironment of ovarian cancer cells is rich in androgens, and high levels have also been reported in ascitic fluid (Helzlsouer et al., 1995). These observations are consistent with the hypothesis that androgens, which are present in the ovarian stromal environment, predispose the OSE to neoplastic conversion and/or ovarian cancer progression (Scully, 1995; Risch, 1998; Ghahremani et al., 1999). The mechanism of action of androgen/AR has been intensively studied in prostate cancer. In addition to classical ligand-dependent genomic action, AR can be activated in a ligand-independent manner by a number of cellular factors including growth factors, IL-6 and activators of the PKA pathway. Moreover, some cellular regulators can potentiate AR activity induced by low doses of androgen in prostate cancers (Culig et al., 1994; Nazareth and Weigel, 1996; Darne et al., 1998; Craft et al., 1999; Chen et al., 2000; Wen et al., 2000).
In normal human OSE cells, 5-dihydrotestosterone (DHT) was found to be more effective than testosterone in stimulating cell growth, whereas they were equally potent in ovarian cancer cells. Androgen-induced cell growth can be reversed by co-treatment with the anti-androgen, 4-hydroxy flutamide. DHT and testosterone increased the level of IL-6 mRNA and protein which contributed to androgen-induced proliferation in ovarian cancer cells, but not in normal human OSE cells (Syed et al., 2001, 2002). Recent studies indicate that there is no relationship between AR repeat length and the presence of BRCA mutation. However, ovarian cancer patients from both groups (with or without BRCA mutation) who carried a short AR allele were diagnosed an average of 7.2 years earlier than patients who did not, suggesting that AR allele length affects the age of diagnosis of ovarian cancer, irrespective of BRCA mutation status (Levine and Boyd, 2001).
In SKOV-3 cells and primary ovarian cancer cells from ascites, DHT blocks the anti-proliferative effects of TGF-ß1, in part, via modulation of TGF receptors, suggesting that androgens may facilitate the escape of ovarian cancer from the potent growth-inhibitory effects of TGF. It is of interest that treatment of SKOV-3 and HEY cells with DHT and its antagonist flutamide resulted in a dose-dependent down-regulation of TGFR-II mRNA (Evangelou et al., 2000). The agonist activity of flutamide in SKOV-3 and HEY cells may be due to their expression of AR–associating protein (ARA)-70 and SRC-1, which have been reported to amplify AR transactivation and to result in agonist activity of AR antagonists (Evangelou et al., 2003). Interestingly, TGF-ß receptor, SRC-1 and ARA-70 transcripts were found to be regulated in a coordinated manner by androgen in normal cells, but not in malignant cells. These findings raise the possibility that ovarian carcinogenesis may involve the modulation of steroid receptor co-activator expression.
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Concluding remarks |
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TOPAbstractIntroductionPeptide hormones in OSE...Steroid hormones in OSE...Concluding remarksReferences |
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The epithelial ovarian carcinomas encompass a diverse, biologically complex, group of malignant neoplasms with a dismal clinical prognosis. There is an urgent need for a better understanding of their source, the OSE, and its propensity to neoplastic progression. As reviewed above, there is increasing evidence implicating a role of several key reproductive hormones in ovarian cancer development and/or progression. The work of our laboratory and others to date has indicated that the effects of GnRH, gonadotrophins, activin/inhibin and steroid hormones on the regulation of ovarian cancer cell growth and/or apoptosis may involve other growth factors and may be mediated by a complex array of intracellular signalling pathways (Figure 4). It is important that we gain a thorough understanding of how these hormones exert their effect on the OSE, especially in view of the rapid increase in ovarian cancer incidence after menopause and the potential risk associated with infertility drugs. The continued characterization of the molecular and signalling mechanisms underlying the stimulatory or inhibitory actions of these hormones in the growth, differentiation and progression of OSE to ovarian cancer should bring about a better understanding of ovarian carcinogenesis. It will provide an opportunity for the development of preventive and/or therapeutic approaches targeting signal transduction pathways or key molecules (i.e. hormone receptors). Further studies will be needed to identify hormonal components that determine the phenotype of OSE from women with or without family histories of ovarian cancer. This knowledge may lead to the identification of new and clinically useful detection markers for the regulation of ovarian cancer growth and for new approaches to adjuvant therapy of these neoplasms.
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TOPAbstractIntroductionPeptide hormones in OSE...Steroid hormones in OSE...Concluding remarksReferences |
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This work was supported by the Canadian Institutes of Health Research. PCKL is a Distinguished Scholar of the Michael Smith Foundation for Health Research. JHC is recipient of a studentship award from the CIHR Interdisciplinary Research Training Program of Women’s Reproductive Health. We thank Dr Christian Klausen for his critical comments and review of the manuscript.
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References |
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