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Reproductive Endocrinology |
Department of Obstetrics and Gynecology, Kobe University School of Medicine, Kobe, Japan
Address all correspondence and requests for reprints to: Takeshi Maruo, M.D., Department of Obstetrics and Gynecology, Kobe University School of Medicine, 7–5-1 Kusunoki-cho, Chuo-ku, Kobe 650, Japan.
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Introduction |
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Homeostatic control of the net growth of tumors is thought to be the result of the dynamic balance between cell proliferation and cell death, and too much growth can come from too little death as well as from too much proliferation (9). Only several years ago, many researchers trying to understand what causes the growth of tumors focused their attention on the pathways within cells that tell them when to divide. However, recent work is showing that cells also have internal pathways that tell them when to die (10). It is possible that in tumors the death pathway may be suppressed, extending the lives of the cells. Actually, apoptosis or programmed cell death is known to occur in tumors either spontaneously or in response to treatment (11, 12).
Recent research efforts have focused on the function of protooncogene and tumor suppressor gene products in directing cell fate. In particular, an explosion of research interest has centered around the role of Bcl-2 in controlling the survival and death of cells. The bcl-2 protooncogene was discovered in lymphoma tumors composed of B cells (13). It is now evident that the bcl-2 protooncogene encodes a 26-kDa protein, localized to mitochondrial and perinuclear membranes. The product of the bcl-2 gene, when elevated in cells either in vivo or in vitro, prevents the normal course of apoptotic cell death in a variety of cells induced by tropic factor deprivation or other stimuli without altering proliferation (14, 15). In addition to extending the life span of certain cells, Bcl-2 protein can promote cell replication by reducing the requirements for growth factors (16, 17). It seems, therefore, that Bcl-2 protein may play an important role in the growth of tumors. However, to date, no information is available on the expression of Bcl-2 protein in uterine leiomyomas. Thus, we conducted the present studies first to determine the expression of Bcl-2 protein in leiomyomas in comparison with that in the normal myometrium by means of immunohistochemical techniques and immunoblot analysis with a monoclonal antibody to human Bcl-2 protein. Furthermore, to understand the role of ovarian steroids in regulating the expression of Bcl-2 protein in uterine leiomyomas, we examined whether ovarian steroids could influence the levels of Bcl-2 protein expression in leiomyoma cells cultured in vitro under a serum-free, phenol red-free condition.
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Materials and Methods |
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Phenol red-free DMEM (18, 19) and antibiotic solution (1 x 105 U/L penicillin and 50 mg/L streptomycin) were purchased from Life Technologies (Grand Island, NY). FBS, 17ß-estradiol (E2), and progesterone (P4) were obtained from Sigma Chemical Co. (St. Louis, MO). Collagenase was purchased from Wako Pure Biochemical Industry (Osaka, Japan). Monoclonal antibodies to human cytokeratin 19 and human desmin were purchased from Nichirei Corp. (Tokyo, Japan). Monoclonal antibody to human vimentin was purchased from Sigma Chemical Co. (St. Louis, MO). Monoclonal antibody to human Bcl-2 protein was purchased from Dako Corp. (Carpinteria, CA). The 75-cm2 flasks were purchased from Iwaki Glass Corp. (Chiba, Japan).
Tissue collection
Uterine leiomyomas and adjacent normal myometrial tissues were obtained from women with regular menstrual cycles who underwent abdominal hysterectomy for medically indicated reasons at Kobe University Hospital. The use of uterine tissues for culture experiments was approved by the institutional review board. The patients ranged in age from 30–43 yr with a mean age of 37 yr, and none had received hormonal therapy for at least three cycles before surgery. Informed consent was obtained from each patient before surgery for the use of uterine tissues for the present studies. Samples were excluded if accurate menstrual cycle dates could not be assigned or if unexpected pathology was found (e.g. adenomatous hyperplasia). Each uterine specimen was examined by a pathologist for histological examination and dating of the endometrium. Endometrial tissues were obtained from the extirpated uteri, and the day of the menstrual cycle was determined by endometrial histological dating according to the method of Noyes et al. (20) and the patient’s last menstrual period. A total of 30 uterine leiomyomas and myometrial tissues were collected, of which 11 were from the proliferative phase and 19 from the secretory phase of the menstrual cycle.
Immunohistochemical staining
Uterine tissue specimens obtained were fixed in 4% buffered neutral formaldehyde solution, dehydrated, and embedded in paraffin. Sections, 5–6 µm thick, were deparaffinized and followed by standard histological techniques. Immunohistochemical staining was performed by the avidin/biotin immunoperoxidase method with the use of a polyvalent immunoperoxidase kit (Omnitags, Lipshow, MI) as previously described by Maruo and Mochizuki (21). A mouse monoclonal antibody to human Bcl-2 protein was used as the primary antibody in this study. To assure the specificity of the immunological reaction, adjacent control sections were subjected to the same immunoperoxidase method, except that the primary antibody was replaced by nonimmune murine IgG (Miles, Erkhardt, IN) at the same dilution as the specific antibody. In the control experiments, the replacement of the specific primary antibody with nonimmune murine IgG resulted in a lack of positive immunostaining. The intensity of immunostaining was evaluated by repeated staining of the same specimens and by more than two observers. It was graded as (-) for no immunostaining, (+) for weak but definitely detectable immunostaining, (++) for moderate immunostaining, and (+++) for intense immunostaining.
Cell culture
Uterine leiomyoma tissues and adjacent normal myometrial tissues obtained in the proliferative phase and secretory phase of the menstrual cycle were, respectively, dissected from endometrial cell layers, washed in PBS, cut into small pieces, and digested in 0.2% collagenase (wt/vol) at 37 C for 3–5 h (22). The leiomyoma cells and myometrial cells were collected by centrifugation at 460 x g for 5 min and washed several times with DMEM containing 1% antibiotic solution. The isolated leiomyoma cells and myometrial cells were, respectively, plated in 75-cm2 flasks at approximate density of 5 x 105 cells/flask and subcultured for 120 h at 37 C in a humidified atmosphere of 5% CO2-95% air in DMEM supplemented with 10% FBS (vol/vol). The trypan blue exclusion test was used to determine the cell viability. Characterization of the cultured cells was examined using immunostaining with monoclonal antibodies to a muscle-specific protein desmin, to a class of intermediate filament protein present in fibroblast vimentin, and to a cytoskeletal protein for epithelial cells cytokeratin 19. Thereafter, the cultured cells were stepped down to serum-free conditions by incubating in serum-free DMEM in the presence or absence of P4 or E2. Treatment with P4 or E2 was begun when the cultured cells were at approximately 40–50% confluence, and monolayer cultures were maintained in serum-free DMEM for an additional 72 h.
Protein extraction and Western immunoblotting
At the termination of cultures, cultured cells were incubated at 4 C for 15 min in the presence of a lysis buffer consisting of 150 mmol/L NaCl, 1% Nonidet P-40, 0.5% deoxycholate, 0.1% SDS, 50 mmol/L Tris-HCl, and 2 mmol/L phenylmethylsulfonylfluoride, pH 7.5. Cells were subsequently scraped off the plates, the extracts were centrifuged at 13.000 x g for 30 min, and the supernatants were collected. On the other hand, leiomyomas and adjacent normal myometrial tissues for protein extraction were collected immediately after hysterectomy. These tissue samples were homogenized at 4 C in the above-noted lysis buffer (5 g tissue in 1–2 mL). Homogenates were subsequently centrifuged at 13,000 x g for 30 min, and the supernatants were collected. Protein estimation of the supernatants was performed by the Bradford assay (23).
Each of 150-µg aliquots of proteins extracted from cultured cells and uterine tissues was run on a 10% SDS-polyacrylamide gel under a reducing condition using 20–25 milliamperes (mA) for the stacking gel and 30–35 mA for the separating gel for 3–4 h. The proteins were electrophoretically transferred from gels to nitrocellulose membranes overnight at 30 mA as previously described (24). Blots were exposed overnight to the monoclonal antibody directed against Bcl-2 protein at a dilution of 1:80 in Tris buffer. The antigen-antibody complexes were detected with the secondary antibody using the ECL chemiluminescence detection system (Amersham, Arlington Heights, IL). Control procedures for Western immunoblotting included the substitution of the primary antibody with nonimmune murine IgG and omission of the primary antibody. These controls prevented the appearance of immunoreactive Bcl-2 protein band of the membrane-bound proteins.
These experiments were repeated as followed with similar results, and the reported results are representative. Western blot analysis of leiomyoma and myometrium tissue extracts with a monoclonal antibody to Bcl-2 protein were performed six times using six different uterine specimens. Three experiments were performed with uterine specimens obtained in the proliferative phase of the menstrual cycle, and the other three experiments were conducted with uterine specimens obtained in the secretory phase of the menstrual cycle. On the other hand, experiments to investigate the effects of sex steroids on Bcl-2 protein expression in cultured leiomyoma cells were performed four times. Two experiments were performed using leiomyoma cells obtained in the proliferative phase of the menstrual cycle, and the other two experiments were conducted using leiomyoma cells obtained in the secretory phase of the menstrual cycle.
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Results |
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), but was scarcely present in normal myometrial
smooth muscle cells (Fig. 1B). Replacement of the primary antibody with
nonimmune murine IgG resulted in a lack of positive immunostaining in
the leiomyoma cells (Fig. 1C). Comparison between immunostaining for
Bcl-2 protein in leiomyoma tissues obtained in the proliferative phase
(Fig. 2A) and for Bcl-2 protein in tissues from the
secretory phase (Fig. 2B) showed that Bcl-2 protein expression in the
leiomyoma cells in the secretory phase was much more abundant than that
in the proliferative phase of the menstrual cycle. By contrast, there
was no apparent difference in the intensity of immunostaining for Bcl-2
protein in normal myometrial smooth muscle cells between the
proliferative phase (Fig. 2C) and the secretory phase of the menstrual
cycle (Fig. 2D). Table 1 summarizes the immunostaining
of Bcl-2 protein in leiomyoma and myometrium in the proliferative phase
and the secretory phase of the menstrual cycle.
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). Leiomyoma tissue extracts showed
a single immunoreactive band with a molecular mass estimate of
approximately 26 kDa. Unlike the leiomyoma tissue extracts, no
immunoreactive band was visualized with myometrial tissue extracts,
indicating that Bcl-2 protein expression in myometrium was below the
sensitivity of the ECL chemiluminescence detection system used. Similar
results were obtained with the use of protein extracts of leiomyoma and
myometrial tissues obtained in the secretory phase of the menstrual
cycle.
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), but not
immunostained with antibodies to either cytokeratin 19, a cytoskeletal
protein specific for epithelial cells (Fig. 4B), or vimentin, a class
of intermediate filament protein present in fibroblasts (data not
shown). The patterns of immunostaining were consistent, as cultures
were monitored with these antibodies regularly.
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). In
contrast, the addition of E2 (10 ng/mL) to the serum-free
medium resulted in a somewhat lower expression of 26-kDa Bcl-2 protein
in the cultured leiomyoma cells relative to that in the leiomyoma cells
in control cultures (Fig. 5). There were no apparent differences in the
effects of sex steroids on Bcl-2 protein expression between leiomyoma
cells obtained in the proliferative phase and those from the secretory
phase of the menstrual cycle. Unlike the cultured leiomyoma cells,
neither treatment with P4 nor treatment with E2
affected the expression of Bcl-2 protein in cultured normal myometrial
cells (data not shown).
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Discussion |
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The growth of uterine leiomyomas in vivo has been shown to be dependent on the presence of ovarian steroid hormones. The increased incidence of leiomyomas after the menarche, the enlargement of leiomyomas during pregnancy, and the regression of leiomyomas after the menopause are clinically evident (3, 4). Actually, tissue concentrations of estrogen receptors and P4 receptors have been shown to be higher in leiomyomas than in normal myometrium (33, 34). Tamaya et al. (35) found that the ratio of estrogen receptor level to P4 receptor level was higher in leiomyomas than in normal myometrium and suggested that the relative increase in estrogen receptors in leiomyoma cells may account for an enhancement of their estrogen sensitivity. On the other hand, Kawaguchi et al. (36) reported that the growth of leiomyoma cells was dependent not only on the presence of estrogen, but also on P4 in an in vitro explant culture system.
With respect to the participation of P4 in the growth of leiomyomas, mitotic activity in uterine leiomyoma of patients treated with a progestin-only preparation has been shown to be significantly higher than mitotic activity in those receiving a combined estrogen-progestin preparation or that in control subjects (37). It is also noteworthy that mitotic activity in uterine leiomyomas is significantly higher in the secretory, P4-dominated, phase of the menstrual cycle than in the proliferative phase (38). The increased mitotic activity in leiomyomas under the hormonal milieu of P4 dominance suggests that leiomyoma growth may also be affected by P4.
In this respect, it is of great interest that treatment with P4 (100 ng/mL) resulted in a striking increase in the expression of Bcl-2 protein in leiomyoma cells cultured under serum-free, phenol red-free conditions, whereas treatment with E2 (10 ng/mL) resulted in a somewhat lower expression of Bcl-2 protein in the cultured leiomyoma cells relative to that in control cultures. As Eiletz et al. (39) reported that P4 levels in human myometrium and leiomyoma tissues were as high as 10–70 ng/g protein, whereas E2 levels in human myometrium and leiomyoma tissues ranged from 4–10 ng/g protein, the concentrations of sex steroids used in the present study appear to be within the physiological tissue concentration range. The fact that Bcl-2 protein expression in cultured leiomyoma cells was remarkably augmented by P4 is consistent with our immunohistochemical observation of higher expression of Bcl-2 protein in leiomyomas in the secretory, P4-dominated, phase of the menstrual cycle compared to that in the proliferative phase of the menstrual cycle. The molecular basis for P4 action in the regulation of leiomyoma growth is not clear, but probably involves the P4-stimulated induction of Bcl-2 protein in leiomyoma cells. Since Bcl-2 product has been shown to prolong cell survival by preventing apoptotic cell death (14, 15), it is likely that P4 may act as a growth-promoting factor in regulating leiomyoma growth through the enhanced inhibition of apoptosis of leiomyoma cells. On the other hand, E2 inhibited the induction of Bcl-2 protein in leiomyoma cells. These results suggest that Bcl-2 protein expression in uterine leiomyoma cells may be regulated by sex steroid hormones. To further understand the effects of sex steroid hormones on uterine leiomyoma growth, it will be needed to examine the effects of combined treatment with E2 and P4 on Bcl-2 protein expression in cultured leiomyoma cells. An inverse relationship between Bcl-2 expression and sex steroid hormones has been described in the endometrium. Up-regulation of Bcl-2 expression by E2 and down-regulation by P4 have been shown in the normal endometrium (40). Thus, it must be emphasized that the effects of sex steroid hormones on Bcl-2 protein expression vary among the different cell types even in the uterus. Indeed, in cultured normal myometrial cells, neither treatment with P4 nor that with E2 affected the expression of Bcl-2 protein, as assessed by Western immunoblot analysis. Furthermore, there was no apparent difference in the immunohistochemically detected cellular levels of Bcl-2 protein in normal myometrial smooth muscle cells between the proliferative phase and the secretory phase of the menstrual cycle. This suggests that no cyclic changes in Bcl-2 protein expression exist in the normal myometrium throughout the menstrual cycle.
In conclusion, we have demonstrated greater abundance of Bcl-2 protein in leiomyomas relative to the normal myometrium of the same individual uterus and that Bcl-2 protein expression in leiomyoma cells predominated in the secretory, P4-dominated, phase of the menstrual cycle compared to that in the proliferative phase. Consistent with these findings, Bcl-2 protein expression in leiomyoma cells cultured in vitro under serum-free, phenol red-free conditions was up-regulated by P4, but down-regulated by E2. It seems, therefore, likely that P4 may participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells, whereas E2 may participate in leiomyoma growth through the stimulation of proliferative potential of leiomyoma cells (Maruo, T., unpublished data) rather than by inhibition of the apoptosis of leiomyoma cells. The abundant expression of Bcl-2 protein in leiomyoma may be one of the molecular bases for the enhanced growth of leiomyoma relative to that of normal myometrium in the uterus.
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Footnotes |
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Received July 11, 1996.
Revised August 19, 1996.
Accepted August 28, 1996.
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is a potential mediator of
estrogen action in the mouse uterus. Endocrinology 131:1657–1664.
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