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Department of Surgical Sciences (F.P.), Chair of Obstetrics and Gynecology, University of Udine, Udine, Italy; Institute of Obstetrics and Gynecology (P.F., S.L., R.G., A.G., A.R.G.), University of Pisa, Pisa, Italy; Auxologic Institute (P.V., A.M.D.B), University of Milano, Milano, Italy; and The Clayton Foundation Laboratories for Peptide Biology (W.V.), Salk Institute, La Jolla, California
Address all correspondence and requests for reprints to: Felice Petraglia, M.D., Department of Surgical Sciences, Chair of Obstetrics and Gynecology, University of Udine, piazzale S. Maria della Misericordia, 33100 Udine, Italy.
Abstract
Inhibins and activins are growth factors belonging to the transforming growth factor-ß) family and are known to influence cell proliferation and differentiation. Because transforming growth factor-ß is involved in physiological and tumoral changes of uterine tissues, the present study aimed to evaluate whether human normal and neoplastic endometrial and cervical epithelial cells express and secrete inhibin A, inhibin B, and activin A.
To test this hypothesis, different approaches were used. By RT-PCR, the
expression of specific messenger RNAs (mRNAs) for the inhibin 
,
activin ßA and ßB subunits, and activin receptor type II and type
IIB was investigated: 1) in primary cultures of endometrial (stroma and
epithelium) or cervical (epithelium) cells from healthy women; and 2)
in specimens of endometrial or cervical carcinoma. To demonstrate a
possible secretion of the proteins, dimeric inhibin A, inhibin B, and
activin A were measured in culture medium of normal epithelial or
stromal endometrial cells and in uterine washing fluid of healthy women
or patients with endometrial adenocarcinoma. Levels of the proteins
were also measured in serum of women with endometrial or cervical
carcinoma.
Cultured endometrial stromal or epithelial cells and epithelial
cervical cells expressed inhibin , activin ßA and ßB, and
activin receptor type II and type IIB mRNAs. The same finding was
obtained in specimens of endometrial or cervical carcinomas.
Dimeric inhibin A, inhibin B, and activin A were measured in culture medium of both endometrial and cervical cells. In particular, resulting activin A levels were significantly higher in epithelial than in stromal cultured endometrial cells (P < 0.01). Dimeric proteins were also detected in the washing fluid of the uterine cavities of healthy women (controls) and with endometrial adenocarcinoma, in which higher activin A levels were found (P < 0.01 vs. controls). Women with endometrial carcinoma showed serum activin A levels significantly higher than healthy controls (P < 0.01), which significantly decreased after surgical removal of endometrial or cervical tumors (P < 0.01).
The present study, for the first time, showed that inhibin A, inhibin B, and activin A, as well as activin receptors, are expressed in normal and neoplastic human uterine tissues. A secretion of activin A from tumoral cells into systemic circulation is suggested by the observation that the high levels in serum of patients with endometrial or cervical carcinoma decreased after the surgical removal of the tumor.
THROUGHOUT the menstrual cycle, human uterine endometrial and cervical epithelia undergo a process of proliferation, differentiation, and active secretion, to create a favorable environment for sperm transport and embryo implantation. Sex steroid hormones, growth factors, and proteolytic enzymes modulate physiological and neoplastic tissue remodeling and neovascularization. Transforming growth factor-ß (TGF-ß) is locally expressed (1, 2, 3) and is an important regulator of cell growth and proliferation in normal and tumoral endometrial and cervical epithelia (4, 5, 6).
Inhibin and activin are dimeric glycoproteins, belonging to the TGF-ß family, that were initially isolated from the gonads and identified as modulators of FSH production and secretion from the anterior pituitary gland (7). Later, several studies have demonstrated that these proteins are widely expressed in different tissues and act as growth factors influencing cell proliferation and differentiation (8). The expression and secretion of inhibin and related peptides in various gonadal and nongonadal tumors is currently investigated (9, 10, 11, 12, 13, 14, 15). Indeed, benign (pituitary adenoma) or malignant (ovary, prostate, placenta, adrenal, liver, kidney, and brain) tumors express inhibin and activin subunit mRNA (11, 12, 13, 14, 15). Moreover, a secretion of inhibins and activins from tumors into systemic circulation is suggested by the high serum immunoreactive inhibin levels in women with ovarian or placental carcinoma (9, 10) and by the high levels of serum activin A in subjects with solid cancer (16).
The aim of the present study was to investigate whether human normal and tumoral endometrial and cervical epithelia express inhibins and activins. With this purpose we studied: 1) the expression of inhibin and activin subunit and activin receptor mRNA expression and protein secretion in cultured human endometrial or cervical cells; 2) the expression of inhibin and activin subunit mRNAs in adenocarcinoma cell lines and in specimens of endometrial or cervical carcinoma; and 3) the possible secretion of dimeric inhibin A, inhibin B, and activin A in uterine washing fluid or in serum of patients with endometrial or cervical carcinoma.
Materials and Methods
Subjects
A group of young, healthy women (n = 6; age range, 25–32 yr), who underwent a hysteroscopy for fertility screening, were enrolled. Specimens of normal endometrium were obtained from subjects at the mid-late proliferative phase (days 10–12; n = 3) or at the midsecretory phase (days 20–23; n = 3) of the endometrial cycle. To obtain cervical epithelium, biopsies were derived from hysterectomy specimens performed in women with uterine fibromata (n = 3; age range, 41–43 yr). In the clinical history of these subjects, the absence of infections or neoplastic diseases was the exclusion criterion.
A group of women with endometrial (n = 25; age range, 45–80 yr) or cervical carcinoma (n = 10; age range, 25–61 yr) was enrolled at the time of the diagnosis. A serum specimen was collected before any medical or surgical treatment. In 10 of 20 women with endometrial carcinoma and in all women with cervical carcinoma, a serum sample was collected 1 month after surgical removal of the tumor. Pathological diagnosis were done on hysteroscopic or hysterectomy specimens. According to the criteria of the International Federation Gynecology and Obstetrics, they were classified: endometrial adenocarcinoma [well = 9 (G1); moderate = 9 (G2); and poorly differentiated = 7 (G3)], cervical squamous carcinoma (G2 = 3; G3 = 5), or adenocarcinoma (G2 = 2). Tumoral cells for evaluating the expression of inhibin and activin subunit mRNAs were collected from hysterectomy specimens in a group of women with endometrial adenocarcinoma (n = 5), cervical adenocarcinoma (n = 2), and cervical squamous cercinoma (n = 3). In a subgroup of 5 patients with endometrial adenocarcinoma, a specimen of uterine washing fluid was collected at hysteroscopy.
A group of healthy age-matched women (n = 25; age range, 45–75 yr) served as control. A specimen of serum and uterine washing fluid (n = 5) was collected from these women. Patients and controls were in postmenopause, with low levels of circulating estradiol and increased serum levels of FSH. All subjects gave their informed consent, and the permission of the Human Investigation Committee was granted.
Cell cultures
Endometrial tissue specimens were minced into small pieces and incubated for 2 h at 37 C in a shaking water bath in 10 mL Ham’s F-10 containing 0.1% collagenase. Epithelial glands and stromal cells were then separated by differential sedimentation at unity gravity and selective plating on plastic substrate. Dissociation of epithelial glands in single cells was achieved by digesting the pellet in a 0.05% trypsin solution for 3–5 min. Epithelial and stromal cells were cultured in Ham’s F-10 medium supplemented with 10% FCS and antibiotics (17). Diffuse cytoplasmic immunostaining for vimentin and cytokeratin was present in most (90%) cultured stromal and epithelial cells. The cytofluorimetric analysis indicated that macrophage contamination was less than 2%. Primary cultures were used within 3 days from cell dispersion. The cells were cultured in 60-mm dishes, and cell density was 1.0 x 106/dish.
Cervical epithelial cells were trypsin-disaggregated and plated as previously reported (18). They were incubated in Ham’s F-10 medium supplemented with 10% FCS and antibiotics. Cells were used for the experiments within 3 days from the dissociation procedure. The cells were cultured in 60-mm dishes, and cell density ranged between 6.0 x 105/dish and 1.0 x 106/dish.
As positive control, cultured trophoblast cells, collected from healthy pregnant women (n = 3) at term (39–40 weeks of gestation), were used within 3 days from cell preparation (19).
In addition, two endometrial adenocarcinoma cell lines, HEC 1A and HEC 1B, were obtained from the American Type Culture Collection (Rockville, MD) and processed. Cell density was 1.0 x 106/dish.
RNA preparation
Harvested cultured cells and tumoral tissue specimens were treated for extraction of total RNA, using the method of Chomiczynski and Sacchi (20), and were quantified by UV absorption at 260 nm.
RT-PCR
The expression of inhibin , activin ßA, activin ßB, and
activin receptor mRNAs was demonstrated by amplifying respective target
sequences by PCR, according to the instructions of the GeneAmp
amplification reaction kit (Perkin Elmer, Milano, Italy). Total RNA (2
µg) was reverse transcribed to prepare complementary DNA (cDNA). PCR
was performed by using Taq (Thermus acquaticus) DNA
polymerase.
Reaction conditions for reverse transcription were: 1 mmol/L deoxynitrophenyl triphosphate, 1 U of RNAsin, 100 pmol of random hexamers, and 200 U of RT. The reaction was run at 42 C for 1 h, and at 94 C for 5 min. Then the mixture was quick-chilled on ice.
The specific oligonucleotide primers, designed to amplify sequences of
inhibin (21), activin ßA (22), activin ßB (22), and activin
receptor type II (ActRII) and type IIB (ActRIIB) (23) cDNAs, are shown
in Table 1
. Computer analysis, performed
to study the secondary structure of the different cDNAs and to compare
the synthesized oligomers with the human sequences in the MicroGenie
(Beckman, Palo Alto, CA) gene database bank, revealed no more than 74%
homology in the former and 72% in the latter, among all the other
genes. Sequence homology among the different oligomers used in the
present study was avoided, excluding possible cross-reactions. For
inhibin and activin ßA subunits, cDNA amplification was performed
with 35 thermal step cycles (94 C, 1 min; 60 C, 1 min; 72 C, 3 min);
whereas for activin ßB, 40 thermal step cycles (94 C, 1 min; 60 C, 2
min; 72 C, 3 min) were used. For activin receptors, we followed 3
thermal step cycles (94 C, 30 sec; 37 C, 30 sec; and 72 C, 1 min, with
2 min ramp time) followed by 30 cycles (ActRII: 94 C, 30 sec; 62 C, 7
sec; and 72 C, 1 min) (ActRIIB: 94 C, 30 sec; 60 C, 7 sec; and 72 C, 1
min). For each tissue analyzed, the template was omitted in the
amplification mixture during the RT-PCR, to rule out DNA contamination,
and was used as negative control.
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Collection of fluids
Blood samples (12 mL) were collected in the morning (between 0800 and 0900 h) from the antecubital vein and were allowed to clot. After centrifugation (3000 rpm x 15 min), serum was divided into three aliquots and was stored at -20 C until assay.
Uterine fluid was collected using a pediatric Foley catheter. The catheter was inserted into the uterine cavity, and the balloon of the catheter was inflated with 1 mL of normal saline solution. The same solution (2 mL) was then gradually flushed into the uterine cavity via the opening connected to the inner lumen; afterwards, gentle suction via the same opening was applied to recover the fluid. The washing fluid was centrifuged (3000 rpm x 10 min) to discharge the cellular component, then stored at -20 C until assay.
Culture medium (1 mL) was collected after 3 or 6 h incubation, in the absence of FCS, and was centrifuged (3000 rpm x 10 min) and stored at -20 C until assay.
Inhibin A, inhibin B, and activin A assays
Inhibin A, inhibin B, and activin A concentration in the various fluids (culture medium, washing fluid, and serum) was measured using specific two-site enzyme immunoassays, as previously described (purchased from Serotec, Oxford, UK) (24, 25, 26). Briefly, in each assay, standard and samples were diluted, as appropriate, and mixed with an equal volume of distilled water containing 10% SDS. After 3 min at 100 C, tubes were cooled before adding freshly prepared hydrogen peroxide solution. After an additional time of incubation at room temperature, duplicate aliquots of denatured and oxidized samples/standards were transferred to antibody-coated microtiter plates. Plates were incubated at room temperature for 2 h (inhibin A) or overnight (inhibin B, activin A). After washing with a phosphate buffer, 50 µL alkaline phosphatase-conjugated extravidin were added, and plates were incubated for 1 h (inhibin A), 2 h (activin A), or 3 h (inhibin B). Plates were washed, and bound alkaline phosphatase was quantitated using a commercially available enzyme immunoassay amplification kit (Immuno Select ELISA Amplification System, Dako, Milano, Italy), which was used according to the supplier’s instructions. The inhibin A detection limit was 4 pg/mL serum, with intra- and interassay coefficients of variations (CVs) for quality control samples of 4.0% and 8.0%, respectively. The assay detection limit for inhibin B was less than 10 pg/mL. Within- and between-plate CVs, in this case, were less than 5.0% and 9.0%, respectively. The limit of detection for activin A was 10 pg/mL, and intra- and interassay CVs were 5.0% and 9.0%, respectively. Cross-reactions for each assay, with the the various inhibin-related proteins, were less than 0.5%.
Statistical analysis
The results were evaluated using ANOVA for multiple comparison and the Mann-Whitney U test.
Results
Expression of inhibin and activin subunit mRNAs
RT-PCR analysis showed that cultured human endometrial stromal or
epithelial cells and cultured human cervical cells express specific
mRNAs for inhibin , activin ßA, and activin ßB (Fig. 1). The DNA size corresponds to those
detected in trophoblast cells used as positive controls (Fig. 1).
Furthermore, endometrial stromal or epithelial cells and cervical
epithelial cells also express ActRII and ActRIIB mRNAs (Fig. 1). No
amplified fragment caused by DNA contamination was detected in any
experiment.
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). Endometrial carcinoma cell lines
(HEC-1A and HEC-1B) also expressed the specific mRNAs for inhibin and
activin subunit mRNAs and activin receptor mRNAs (data not shown).
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Medium collected from cultured normal endometrial epithelial or
stromal cells or from cervical epithelial cells contained discrete
amounts of inhibin A, inhibin B, and activin A (Fig. 3). The concentration of activin A, in
culture medium, of endometrial epithelial cells was significantly
higher than in cultured stromal cells (P < 0.01) (Fig. 3). Inhibin A, inhibin B, and activin A in culture medium collected
from HEC-1A (mean ± SEM inhibin A: 4.32 ± 0.008
pg/105 cells; inhibin B: 1.08 ± 0.05
pg/105 cells; and activin A: 0.05 ± 0.004
ng/105 cells) and HEC-1B cell lines (mean ±
SEM inhibin A: 4.62 ± 0.16 pg/105 cells;
inhibin B: 0.89 ± 0.24 pg/105 cells; and activin A:
0.04 ± 0.003 ng/105 cells) also showed measurable
concentration.
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Whereas inhibin A and inhibin B concentration did not show a
significant difference, activin A concentration in fluid collected from
patients with endometrial carcinoma was higher than in controls (Fig. 4).
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No difference was observed for inhibin A and inhibin B levels
between women with endometrial or cervical carcinoma and healthy
controls (Fig. 5). Mean ±
SEM activin A levels in patients with endometrial carcinoma
were significantly higher than in healthy controls (P
< 0.01) (Fig. 5). When measured 1 month after surgery, serum activin A
levels in endometrial or cervical carcinoma significantly decreased
(P < 0.01) (Fig. 6).
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The present study provides substantial evidence that human normal and neoplastic uterine endometrial and cervical cells express the genes for inhibin and activin subunits and secrete dimeric inhibin A, inhibin B, and activin A in culture medium. In addition, the evidence that women with endometrial or cervical carcinoma showed high serum levels of activin A, which decreased after the surgical removal of the tumor, suggests that uterine carcinomas secrete activin A into the circulation.
The expression of inhibin and activin ßA and activin ßB subunit
mRNAs suggests that endometrial cells may synthesize both forms of
inhibin (inhibin A: ßA; and inhibin B: ßB) and the three
forms of activin (activin A: ßAßA; activin AB: ßAßB; and
activin B: ßBßB). The evidence that inhibin A, inhibin B, and
activin A are measurable in the medium of cultured endometrial cells
confirms that at least these three forms are the secretory products of
human endometrium. There are not yet available assays for measuring
activin AB and activin B, which have been also rarely described in
human tissues (27). Because the details on the biosynthetic mechanism
regulating the production of each form of inhibin or activin are not
yet known, it is difficult to speculate on the cellular mechanisms
yielding to protein secretion in uterine tissues. The evidence that
concentration of activin A in culture medium of endometrial epithelial
cells was higher than in stromal cell suggests that endometrial glands
preferentially secrete activin A. An immunohistochemical study,
conducted using a nonspecific antiserum raised against a 10.7-kDa
prostatic inhibin, showed an inhibin-like peptide localized in
glandular epithelium of normal and in hyperplastic and malignant
endometrium (28).
For the first time, we have shown that endometrial and cervical
carcinoma cells express the gene for inhibin and activin ßA and
ßB subunits. The evidence that inhibin A, inhibin B, and activin A
are secreted from HEC-1A and HEC-1B cells in culture medium and are
measurable in uterine fluid of women with endometrial carcinoma
suggests that these proteins may be secreted extracellularly from
tumoral cells.
The biological significance of inhibins and activins in normal and
tumoral uterine epithelia remains to be explained. The present study,
showing that both normal and neoplastic uterine cells express activin
receptor mRNAs, suggests that nonpregnant and neoplastic endometrium
and cervix may represent a target other than a source for activin. In
the other organs expressing inhibin-related proteins and receptors
(pituitary, gonads, placenta, adrenal cortex, and bone marrow) a
modulatory role in cell differentiation and in local secretions has
been shown (29). Locally expressed TGF-ß is involved in modulating
physiological or neoplastic growth and enzyme production of endometrial
or cervical cells (3, 4, 5, 6), and a possible role in the process of
decidualization, local immune function, and tumorogenesis has been
suggested (4). Inhibin , activin ßA, and activin ßB or activin
receptor mRNAs are expressed in maternal decidua (30, 31) and affect
cell-mediated immune function (32, 33, 34), but no specific data on uterine
tissues are available. The implications of inhibins and activins in
endometrial and cervical carcinoma are not yet clear. The constitutive
growth factor production and membrane receptor expression would permit
autonomous growth of cancer cells. An involvement of inhibins and
activins in neoplastic proliferation is supported by the experiments
conducted in inhibin -deficient mice, the homozygotes of which all
develop gonadal tumors (35). Because the -inhibin-deficient mice all
show elevated levels of serum activin A (36), the oncogenic effect may
be caused by a tumor suppressive property of -subunit protein
itself, or to the overexpression and secretion of dimeric activin.
In agreement with this hypothesis, the present study showed that serum levels of activin A are increased in women with endometrial or cervical carcinoma and decrease 1 month after the surgical removal of the tumor, suggesting that uterine tumors may be a source of circulating activin A. The secretion of activin A into the bloodstream is not specific of uterine carcinomas, because serum activin A levels are high also in subjects with other forms of advanced solid cancer (lung, digestive tract, and adrenal gland) (16), and in inhibin-deficient mice carrying gonadal tumors (36). However, we have to remember that our assay detects both bound and free activin A; therefore, it does not allow us to evaluate whether circulating activin A in women with endometrial or cervical carcinoma is biologically active. In fact, the actions of activin are modulated by follistatin, a circulating binding protein that blocks the biological effects of activin in the various target organs (7, 8).
The major source of activin A in normal healthy subjects is still unknown, but the small changes throughout the menstrual cycle (26) and the lack of a significant difference in activin A serum levels between fertile and postmenopausal women seem to exclude the gonads as a major source (16, 26). The present data may allow us to hypothesize an additional contribution by endometrial cells. On the other hand, circulating inhibin A and inhibin B levels in fertile women are almost entirely of ovarian origin and become very low after menopause (25, 37). Our data obtained in control postmenopausal women confirm that, in postmenopause serum inhibin A and inhibin B, levels are in the lowest range, whereas activin A is still measurable (37).
In conclusion, the present study identifies inhibin-related proteins and activin receptors in endometrial and cervical normal and neoplastic cells, and it shows that women with endometrial carcinoma have high levels of circulating activin A, suggesting a possible role of inhibin-related proteins in physiology and pathophysiology.
Acknowledgments
The secretarial work of Mrs. G. Campani (Pisa) and Mrs. P. Londero (Udine) is acknowledged.
Footnotes
1 Presented, in part, at the X Congress of the International Society
for Endocrinology, San Francisco, CA, June 12–15, 1996. This work was
supported, in part, by the National Institute of Health Program Project
Grant HD-13527. 
2 A foundation Research Senior Investigator.
Received October 3, 1997.
Revised December 22, 1997.
Accepted December 29, 1997.
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