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Hum. Reprod. Advance Access originally published online on August 7, 2006
Human Reproduction 2006 21(12):3241-3245; doi:10.1093/humrep/del301
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impact of gonadotrophins and steroid hormones on tumour cells derived from borderline ovarian tumours

Claire Basille1, François Olivennes2, Josyane Le Calvez3, Nadine Beron-Gaillard3, Geri Meduri4, Catherine Lhommé5, Pierre Duvillard6, Jean Benard3 and Philippe Morice1,7

1 Departement de Chirurgie, Institut Gustave Roussy, Villejuif 2 Hopital Cochin, Paris 3 Departement de Biologie et de Pathologie Médicale, Institut Gustave Roussy, Villejuif 4 INSERM Unité 693, Le Kremlin-Bicêtre 5 Departement de Medecine, Institut Gustave Roussy, Villejuif, and 6 Departement de Pathologie, Institut Gustave Roussy, Villejuif, France

7 To whom correspondence should be addressed at: Service de Chirurgie, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: morice{at}igr.fr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
BACKGROUND: Conservative surgery is currently proposed for young patients with borderline ovarian tumours (BOT). For those experiencing infertility, the question of medically assisted procreation is raised. We have evaluated in vitro the proliferation of cultured BOT cells in response to FSH or estradiol (E2). METHODS: Primary cell cultures were prepared from BOT. The presence of FSH and E2 receptors was evaluated by immunochemistry. Cultures in vitro were stimulated with FSH (40 and 200 mUI/ml) or E2 (300 and 2000 pg/ml) for 96 h and proliferation was evaluated with the WST-1 test. RESULTS: Four primary cultures were obtained that expressed FSH and E2 receptors to different extents. Growth was generally similar to controls when treated with either FSH or E2 although 300 pg/ml E2 caused a significant inhibitory effect on cell proliferation (P = 0.035). CONCLUSION: No stimulatory effect of FSH or E2 on cultured BOT cells was found, despite the presence of receptors. Although preliminary, these results suggest that gonadotrophins and E2 could be used in patients experiencing infertility after conservative surgery.

Key words: borderline ovarian tumours/estradiol/FSH/gonadotrophin/infertility


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Borderline ovarian tumours (BOT) frequently affect young women. In some women, infertility is one of the symptoms preceding the diagnosis of BOT (Harlow et al., 1988Go; Whittemore et al., 1989Go; Harris et al., 1992Go; Mosgaard et al., 1998Go; Brinton et al., 2004Go). A conservative treatment is often proposed for young patients with early stage tumours in an attempt to preserve fertility (Morice et al., 2003Go). Unfortunately, even in this subgroup of patients, 30% will experience infertility after conservative treatment of the ovarian tumour. A significant number of women with a previous history of BOT will thus undergo medically assisted procreation protocols to conceive. Ovarian stimulation protocols usually include repeated daily FSH injections for 3–14 days that stimulate ovarian estradiol (E2) hypersecretion.

Gonadotrophins and steroid hormones are involved in the genesis of ovarian carcinoma (Atlas and Menczer, 1982Go; Harris et al., 1992Go; Shushan et al., 1996Go). Recently, the overexpression of FSH receptors (FSHR) has been linked with potential oncogenic pathways (Choi et al., 2004Go). Nevertheless, recent meta-analyses of infertile women after assisted reproductive technology (ART) have concluded that infertility remains the main risk factor of ovarian cancer and that ovarian stimulation does not increase the risk compared with that of infertile women without ART (Ness et al., 2002Go; Kashyap et al., 2004Go). The advisability and safety of the use of gonadotrophins and steroids to restore fertility in BOT patients is thus called into question.

Using an approach designed to mimic ovarian hyperstimulation used in IVF protocols, we have investigated the presence of FSHR and E2 receptors (ER) in four BOT cases and have determined the proliferative response to the corresponding hormones of cultured BOT cells.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Cell culture
A sample of tumour tissue obtained per-operatively was immediately placed in Roswell Park Memorial Institute 1640 (RPMI 1640) medium at 37°C and rapidly dissociated mechanically. After centrifuging, the cell pellet was placed in a bovine cellular matrix-coated cell culture flask. Previous experiments had shown that an extracellular matrix was necessary (Gospodarowicz et al., 1980Go), and so a bovine cornea endothelial cell line was selected to create it. It would not interfere with our experiment as it was not from malignant cells. Proline-free RPMI 1640 culture medium was used to eliminate fibroblasts from the culture (Kao and Prockop, 1977Go). Once cells reached confluence, they were enzymatically dissociated and placed in anotherbovine extracellular matrix-coated flask. The cells were cultured until the third transfer, within 4–6 days, and then frozen.

A histopathological review of the ovarian tumour and peritoneal implants (for Patients 3 and 4) was performed by one of the authors (P.D.) (with the clinical course of the patient masked) (Duvillard, 1996Go). BOT was defined as an ovarian tumour with (i) stratification of the epithelial lining; (ii) formation of microscopic papillary projections; (iii) presence of nuclear atypia and, most importantly, (iv) absence of frank stromal invasion. The staging used was the 1987 International Federation of Gynecology and Obstetrics (FIGO) classification. The stage was determined using the macroscopic description obtained during the surgical procedure and by reviewing the pathology records. Peritoneal implants were classified as non-invasive or invasive, according to the criteria previously described by Bell and Scully (1990)Go.

Immunocytochemistry of cell cultures
The epithelial character of the culture was established by immunocytochemistry. Immunocytochemical staining was performed on cells cultured on Labtek (Nunc) slides after fixing with cold acetone (–20°C) or 2.5 buffered paraformaldehyde. Cells were characterized with a monoclonal cytokeratin-7 antibody (Chemicon, CBL194P) and a fibroblast antibody (Clone 5B5, DAKO). Bound immunoglobulins (Igs) were visualized with a secondary fluorescein isothiocyanate-conjugated goat antibody to murine IgG (Molecular Probe, a-11017).

FSHRs were visualized in cells cultured on Labtek slides fixed with cold acetone, using two previously characterized monoclonal FSHR antibodies, FSHR 323 and FSHR 156 (Meduri et al., 2002Go). Bound Igs were visualized with a standard labelled streptavidin system (LSAB, Dako Cytomaton); aminoethylcarbazole was used as a chromogen. When the antibodies were replaced with non-specific antisera or with non-immune mouse Igs of the same subclass (IgG2 and IgG1, respectively) at the same concentrations, there was no labelling.

Immunohistochemistry of tissue sections
ERs were detected on formaldehyde-fixed tumour tissue sections embedded in paraffin. After removal of the paraffin with toluene, sections were put through a graded alcohol series and standard microwave antigen retrieval for 10 min in pH 6 citrate buffer was carried out. The sections were incubated with the following antibodies: anti-ER{alpha} (Clone 1D5, Dako Cytomaton) and anti-ERbeta (SantaCruz Biotechnologies). Bound Igs were visualized with a commercial labelled streptavidin kit (LSAB2, Dako Cytomaton); aminoethylcarbazole was the chromogen. The expression of receptors was evaluated as the percentage of stained cells observed with a light microscope at x100 and x200 magnification.

Stimulation assays in vitro
About 40 mUI/ml (2.93 mg/ml) or 200 mUI/ml (14.7 mg/ml) of FSH and 300 or 2000 pg/ml of E2 were added 24 and 72 h after inoculating cells in 96-well plates in RPMI 1640 medium supplemented with 20% fetal calf serum. Controls received RPMI 1640 medium alone. Six wells were used for each experiment and performed in duplicate. The total exposure time to hormones was 96 h. We did not determine the doubling time of our primary cell cultures because they were not immortalized. Preliminary experiments enabled us to determine that 1000 cells in each well reached an adequate density, corresponding to good sensitivity of the absorption spectra. Proliferation was evaluated by spectrophotometry using a WST-1 colorimetric test kit (Cell Proliferation Reagent WST-1, Roche, Germany). This system uses the cleavage of WST-1 by mitochondrial dehydrogenases to detect the percentage of metabolically active cells. Absorbance of the dye solution was measured after 2 h of incubation with the WST-1 reagent, according to the manufacturer’s instructions and experimental set-up, at 450 nm with a scanning multiwell spectrophotometer. Mean values of the six wells for each series are given. Each experiment was conducted in duplicate. The control was medium with no added hormone.

Statistical analysis
The mean values of absorbance were compared using a univariate General Linear Model. A Dunnett test with adjustment for multiple comparison was used. The overall significance level was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Conclusion
 Acknowledgements
 References
 
Cell culture
We obtained four primary cultures from BOT that were propagated for at least three transfers (three transfers in three patients and four transfers in the last one). The clinical data of four patients treated for these tumours are summarized in Table I. All patients were afflicted with a serous BOT.


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  		Table I. Clinical characteristics of patients with borderline ovarian tumours

 
Characterization of cultured cells
Cell cultures were positively stained with anticytokeratin 7 that is used to characterize epithelial cells. Antifibroblast staining was negative.

Staining FSHR and ER by immunocyto- and immunohistochemistry
FSHRs were found on cell membranes and inside cells. They were differentially expressed in the four primary cultures (Table II): labelling absent in one (from Patient 2), weak in two (Patients 1 and 4) and strong in Patient 3. ER isoform {alpha} was predominant compared with isoform beta. ER{alpha} was expressed in cell nuclei and also in the stroma in three of four cases. ERbeta was expressed in only one primary culture.


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  		Table II. Receptor expression in borderline ovarian tumours determined by immunochemistry, expressed as percentage of stained cells

 
Stimulation assays in vitro
Absorbance values are shown in Table III. In the fourth primary cell line (4), the number of cells was low, and so, we focused on testing FSH. Results of the statistical analysis are detailed in Table IV. No stimulatory effect versus control was found, whatever the dose of steroid or gonadotrophin used. The only difference concerned the procedure using 300 pg/ml of E2: a significant inhibitory effect on cell proliferation was observed (P = 0.035).


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  		Table III. Spectrophotometric measurement of the proliferation of cell cultures from borderline ovarian tumours exposed to medium alone (RPMI 1640), FSH or estradiol (E2) for 96 h(mean absorbance values ± SEM)

 

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  		Table IV. Statistical analysis of spectrophotometric data (Dunnett test with adjustment for multiple comparison)

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Conclusion
 Acknowledgements
 References
 
We obtained four primary BOT cell cultures whose epithelial nature was shown by immunochemistry. BOT cell lines are very different from ovarian adenocarcinoma cell lines in that their proliferation is low, and so, it is difficult to keep BOT cells in culture. We used no procedure for immortalizing cells that could have altered the original phenotype. Despite repeated attempts, we failed to cultivate mucinous BOT cells. To our knowledge, there is only one published borderline ovarian cell line, whose histological subtype was not mentioned (Tourgeman et al., 2002Go).

We verified the presence of FSHRs and ERs in BOT primary cell cultures. The presence of these receptors has been found in borderline tumours in several studies (Abu-Jawdeh et al., 1996Go; Zheng et al., 2000Go). In our work, FSHRs and ERs were expressed variably (Table II). There was no link between the intensity of receptor staining and clinical aggressiveness, as determined by the disease stage (Stage I versus II/III). All cell lines stained positively for ER{alpha} whereas the ERbeta was barely or not expressed. In normal ovaries, the beta isoform is the predominant form of ER, whereas in ovarian cancer, ER{alpha} increases markedly compared with the ERbeta. The overexpression of ER{alpha} relative to ERbeta has been proposed as a marker of ovarian carcinogenesis (Brandenberger et al., 1998Go; Pujol et al., 1998)Go.

In this study, neither FSH nor E2 exerted evident proliferation effects on any of the four primary cultures tested (Tables III and IV). One of the particularities of the present series is that there were two patients (Patients 3 and 4) with advanced stage BOT (define as BOT with peritoneal implants). Even in such patients, the tumours exhibited no particular sensitivity to hormonal stimulation.

One of the flaws of this study is the absence of a ‘positive control group’ of cells known to be sensitive to E2 or FSH stimulation. A cell line from ovarian carcinoma would be logical because several previous studies in vitro suggest a proliferation effect of FSH and steroid hormones. Early observations attributed a stimulating action on the proliferation of ovarian cancer cell lines to FSH (Simon et al., 1983Go; Ohtani et al., 1992Go; Wimalasena et al., 1992Go; Feng et al., 1996Go; Zheng et al., 2000Go). In addition, according to Zheng et al. (2000)Go, FSH induces a dose–response proliferative effect up to 40 mUI/ml. Concomitantly, Syed et al. tested steroids and gonadotrophins on four normal ovarian epithelial cell primary cultures, immortalized cells and carcinoma cell lines. They showed that they all stimulated proliferation, except high-dose progesterone (Syed et al., 2001Go). This result is in agreement with the E2 dose-dependent stimulation of cell growth in ovarian cancer cell lines (Kraemer et al., 2001Go). Other recent studies in vitro, however, have not demonstrated a clear impact of gonadotrophins on proliferation of ovarian cancer lines. In the study of Tourgeman et al. (2002)Go, three lines were studied: benign cystadenoma, borderline tumour and ovarian carcinoma. Gonadotrophins induced no proliferation in any of these cell lines. An inhibitory effect was even mentioned for FSH on adenocarcinoma cell lines in other studies (Kataoka et al., 1994Go). Karlan et al. (1995)Go found no effect on primary cultures of the ovarian surface epithelium with E2 or progesterone; in fact, an inhibitory effect has even been reported (Wimalasena et al., 1992Go). An inhibitory effect of FSH has been reported on proliferation of the ovarian epithelial surface in culture (Ivarsson et al., 2001Go) or an adenocarcinoma cell line (Kataoka et al., 1994Go). Hence, several published studies in vitro have evaluated the stimulation of malignant ovarian cell lines and ovarian cell primary cultures, but the conclusions differ. The discordance of those results could be because of individual variability of the cells and to the different protocols utilized. These variations in response of positive control cell lines, clearly identified in several studies as being sensitive to growth stimulation by FSH and E2, explains why we did not include a ‘control group’.

The only study concerning one BOT cell line showed that FSH had no stimulatory effect and, on the contrary, that HCG inhibited proliferation (Tourgeman et al., 2002Go). Our study supports these results, showing no proliferation with either FSH or E2. The originality of our study resides in the fact that the cells tested were from primary cultures, with very few secondary transfers; they were thus at early transfers and as close as possible to the initial pathology. The second original feature of our series is the fact that four different BOT cells cultures were tested (instead of one as in the article by Tourgeman et al. (2002)Go.

In clinical practice, there is no consensus concerning women with a previous history of BOT and confronted with problems of infertility. First, case reports have shown the efficacy of IVF for infertile patients after conservative surgery for BOT (Nijman et al., 1992Go; Mantzavinos et al., 1994Go; Hershkovitz et al., 1998Go; Hoffman et al., 1999Go; Chan et al., 2003; Fasouliotis et al., 2004Go). The only case report with a major relapse concerned a patient with an advanced stage micropapillary serous carcinoma, which has the highest risk of malignant transformation (Attar et al., 2004Go). A small series evaluated the relapse rate after IVF procedures as between 0 and 20% (Beiner et al., 2001Go). Most of these patients, however, had relapses in the form of a borderline tumour, easily curable with an exclusive surgery. These rates are consistent with those reported for patients who underwent conservative treatment with no subsequent fertility therapy (Donnez et al., 2003Go), and all cases could have been treated without any impact on the survival rate (Morice, 2006Go). Recently, in a multicentre study including 27 patients from Stage I to Stage III, an 11% relapse rate was observed, with no advancement of the disease at subsequent follow-up (Fortin et al., 2005Go). In our study, using primary cultures from tumours at different—particularly advanced stages—the results argue in favour of the safety of ovarian stimulation after BOT. Our results, however, are based on only four individual cases and thus require confirmation by work on a larger number of primary cultures of BOT. Moreover, the mucinous subtype should also be tested.


   Conclusion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
Acknowledgements
 References
 
BOT primary cultures were stimulated in vitro with E2 and FSH, mimicking ovarian hyperstimulation used in IVF protocols. In the present study, we did not demonstrate any stimulatory effect of FSH or E2 on proliferation of cultured BOT cells. This could argue in favour of ovarian fertility treatments for patients who have undergone conservative management for BOT and are faced with infertility. Our results are to be taken as preliminary in the light of the limited number of cultures, and further studies are required to confirm the results.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
References
 
Thanks to Annie Rey and Serge Koscielny for the statistical analysis.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
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Submitted on March 6, 2006; resubmitted on May 19, 2006; resubmitted on June 28, 2006; accepted on July 3, 2006.


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