Environmental Health Perspectives Volume 108, Supplement 5, October 2000
Pregnancy, Parturition, and Prostaglandins: Defining Uterine Leiomyomas
Kimberley Cesen-Cummings,1 John A. Copland,2 J. Carl Barrett,3 Cheryl L. Walker,1 and Barbara J. Davis1
1Laboratory of Women's Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; 2University of Texas Medical Branch at Galveston, Galveston, Texas, USA; 3Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
Abstract
Leiomyomas, benign smooth muscle tumors of the uterus, are the most common gynecologic neoplasm in women. Studies with surgically resected human tissues and primary cultures have revealed that several genes are differentially expressed in leiomyomas compared to matched normal myometrium. An estrogen-driven pattern of gene expression in leiomyomas, similar to that seen in normal myometrium during pregnancy and parturition, is associated with a persistent inappropriate response of neoplastic myometrial smooth muscle cells to ovarian hormones. This is possibly due to aberrant expression levels or signaling via estrogen and progesterone receptors. We propose the hypothesis that uterine leiomyomas mimic a differentiated myometrial cell at pregnancy and exhibit a hypersensitivity to sex steroid hormones that prevents the cells from responding to normal apoptotic or dedifferentiation signals and from returning to a nongravid phenotype. Support of this hypothesis is derived from experimental studies in female Eker rats that develop uterine leiomyomas with many similarities to the human disease. Our hypothesis accounts for the benign nature of these tumors and their high incidence in women during the reproductive years. By identifying the factors that participate in parturition and involution of the pregnant myometrium, we may better define uterine leiomyomas and thus identify novel targets for therapeutic strategies to treat these tumors.
Key words: cyclooxygenase, differentiation, parturition, prostaglandins, uterine leiomyoma. --
Environ Health Perspect 108(suppl 5):817-820 (2000).
http://ehpnet1.niehs.nih.gov/docs/2000/suppl-5/817-820cesen-cummings/abstract.html
This article is based on a presentation at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research held 7-8 October 1999 in Research Triangle Park, North Carolina, USA.
Address correspondence to B.J. Davis, NIEHS, PO Box 12233, MD B3-06, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-2764. Fax: (919) 541-7666. E-mail: davis1@niehs.nih.gov
The authors thank G. Flake and C. Houle for their critical review of this manuscript.
Received 2 February 2000; accepted 29 June 2000.
Of the many diseases that undermine the health of women, uterine leiomyomas, or fibroids, are the most common tumors affecting the reproductive tract. This disease has a major public health impact because fibroids contribute significantly to infertility and are the leading cause of hysterectomies among premenopausal women in the United States (
1). The primary goals of our research are to understand the fundamental changes in uterine leiomyomas and the environmental impacts in the development of uterine leiomyomas, and to use this knowledge to develop appropriate intervention and prevention strategies to ameliorate the impact of this disease.
Data from our laboratory using animal models and cell culture experiments suggest that leiomyomas have characteristics of well-differentiated uterine smooth muscle cells. Furthermore, these tumor cells have features of smooth muscle of the pregnant myometrium just prior to the onset of parturition. However, a key feature of these tumor cells is that they lack the ability to either produce or respond to prostaglandins, key signaling molecules that mediate the final pathway of parturition. We propose that whereas prostaglandins are responsible for the induction of either apoptosis or dedifferentiation in normal postpartum myometrial cells, leiomyoma cells contain defects in this signaling pathway and thereby persist in a proliferative phenotype.
Throughout pregnancy, human myometrial cells undergo several morphologic changes. The appearance of a hypertrophied myometrial smooth muscle cell of pregnancy is distinctive, exhibiting increased cellular dense bodies and plaques as well as increased collagen deposition and extracellular matrix (
2). Moreover, under the changing hormonal milieu of pregnancy, myometrial cells increase the expression of genes for the gap junction protein connexin 43 (Cx43) and oxytocin receptor (OTR), as well as increase their ability to produce prostaglandins (
3) (Figure 1). The sum of these changes results in functionally differentiated myometrial cells with a hypertrophied, synchronously contractile phenotype.
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Figure 1. Endocrine, paracrine, and autocrine signals initiating labor in the rat. In early pregnancy, high concentrations of serum progesterone maintain uterine quiescence via signaling through myometrial cell progesterone receptors. The concentration of progesterone decreases prior to labor but is not sufficient to induce labor. Uterine excitability and the initiation of parturition in most species occurs when the plasma concentration of progesterone falls below a critical level while that of estrogen rises. Under the stimulation of the rising estrogen concentration, several genes are abundantly expressed. These include OTR, which when bound by oxytocin allows for intracellular calcium stores to be released for muscle contraction, and the gap junction protein Cx43, which is necessary for the synchronicity of the uterine contractions. Finally, at parturition, there is an increase in the production of the excitatory prostaglandins (PGF2 ) catalyzed by the COX enzymes COX-1 and COX-2.
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Andersen and Barbieri described the leiomyoma cell as resembling a myometrial cell of pregnancy rather than a typical myometrial cell of a menstrual cycle (4). These similarities include the increased expression of hormone receptors [estrogen, progesterone, insulinlike growth factor (IGF)-1], growth factors (IGF-1, epidermal growth factor), and extracellular proteins (collagen types I and II). Furthermore, leiomyomas constitutively express high levels of Cx43 (5), the predominant connexin found in the myometrium. Expression of Cx43 is negligible in myometrial cells throughout the menstrual cycle and in early pregnancy. However, beginning about 24 hr before labor, Cx43 becomes abundantly expressed under the influence of estrogen (6). This indicates that leiomyomas not only share the characteristics of myometrial cells during pregnancy, but more specifically, they have the characteristics of myometrial cells immediately before labor.
At parturition and during labor, myometrial smooth muscle cells have a unique phenotype compared to myometrial cells at other stages of pregnancy or during the menstrual cycle. Although this phenotype is similar for leiomyomas, leiomyoma cells differ from the parturient myometrium in that they are neoplastic. The key biochemical and molecular differences between a myometrial cell at parturition and a leiomyoma cell must account for the inability of the leiomyoma cell to remodel after parturition by either apoptosis or dedifferentiation.
Unlike skeletal muscle cells, a feature of smooth muscle cells is their ability to reenter the cell cycle, indicating they are not terminally differentiated (
7) (Figure 2A). Using Balb/c 3T3 mouse proadipocytes as a model, Scott et al. (
8,9) described the cell cycle of differentiated cells to include the G
D and G
D´, phases as components of the first gap of the cell cycle (G
1). G
D represents a distinct G
1 state of growth arrest before cellular differentiation. G
D´ represents the nonterminally differentiated state of the cells. G
D is coupled with the cell cycle to maintain relative equilibrium of the tissue between proliferation, growth arrest, and differentiation. Applying this cell cycle model to human myometrial cells, under the hormonal influences of pregnancy, a smooth muscle cell in the myometrium differentiates to take on the hypertrophied, synchronously contractile phenotype unique to the G
D´ phase of the cell cycle (Figure 2B). Under the different hormonal influences of parturition and involution, populations of myometrial cells either undergo apoptosis or reenter the cell cycle from G
D (Figure 2C). In leiomyoma, however, we propose that entrance into G
D and concomitant differentiation is not equated with growth arrest (Figure 2D). Moreover, with leiomyomas, apoptotic pathways may also be blocked so that proliferating, differentiated cells accumulate, giving rise to benign tumors. Indeed, data demonstrate that human leiomyomas have an increased rate of cellular proliferation and a decreased rate of apoptosis compared to normal myometrium (
10-13).
Figure 2. Comparison of cell cycle progression in myometrial smooth muscle cells versus leiomyoma cells. (A) A feature of smooth muscle cells is their ability to reenter the cell cycle, which has been demonstrated both in vivo and in vitro, indicating that unlike skeletal muscle cells, they are not terminally differentiated. GD and GD´ represent distinct states of growth arrest and nonterminal cellular differentiation. (B) In the myometrium, under the hormonal influences of pregnancy, a majority of smooth muscle cells may differentiate to take on the hypertrophied synchronous contractile phenotype unique to the GD´ phase of the cell cycle. (C) Under the hormonal influences of parturition and involution, populations of myometrial cells may either undergo apoptosis or they may reenter the cell cycle, returning the myometrium to the nongravid phenotype. (D) In benign neoplasms, differentiation may not indicate growth arrest; rather, the differentiated cell may proliferate. In leiomyomas, we propose that entrance into GD and differentiation is irreversible and not coupled with growth arrest. Instead, the nonterminally differentiated cells continue to enter the cell cycle to proliferate. Moreover, with leiomyomas, apoptotic pathways may also be blocked, so differentiated, proliferating cells accumulate, giving rise to benign tumors.
Prostaglandins (PG) stimulate contraction of the pregnant uterus and are the final and common mediators of parturition in all species. In women, all intrauterine tissues are capable of producing prostaglandins, but the fetal membranes, the decidua, and the smooth muscle cells of the myometrium are the sources of prostaglandins at term (
14). Prostaglandins require the cyclooxygenase (COX) enzymes for their production. The COX enzymes are the rate-limiting enzymes in the conversion of arachidonic acid to PGH
2, the precursor to all of the prostaglandins. There are two forms of the enzyme: the constitutive form, COX-1, and the inducible form, COX-2. Normal human smooth muscle cells of the myometrium contain both COX enzymes for the biosynthesis of prostaglandins (
15).
The pregnant myometrium contains approximately 3-fold more total COX protein than a nonpregnant myometrium. Both COX-1 and COX-2 are essential for the normal onset of term labor. COX-1 expression in the myometrium remains relatively stable as pregnancy progresses toward labor (16), and its expression in the myometrium is not altered by either estradiol or progesterone. COX-2 expression in the myometrium is increased throughout gestation and is maximal at the time of delivery (15,16). Expression of the COX-2 enzyme is increased by estradiol in the myometrium, whereas progesterone has no effect on COX-2 expression (14). When COX-2 enzyme expression is maximal and prostaglandin production peaks, parturition occurs and is immediately followed by the process of involution. It is not entirely clear whether involution is a passive process precipitated by the drop of estrogen, progesterone, or their receptors, or if there is a signal to initiate involution. If involution requires an active signal for its initiation, the COX enzymes and the prostaglandins are likely candidates for this role.
The coordinated endocrine and mechanical signals necessary for parturition and involution in the human are similar to those in the rat. Despite significant differences in uterine structure, implantation, gestation, and the maintenance of pregnancy, for example, the smooth muscle cells of the human and rat myometria have similar cellular and molecular properties. These include the increased expression of contractile-associated proteins such as Cx43, OTR, and COX-2 near or at term (17-19). These similarities allow for the use of a rat model to study human parturition, particularly involution at the cellular level.
Uterine involution is characterized by the withdrawal of placental estrogens and progesterone and the reduction of myometrial blood flow (20,21). Many of the pregnancy-regulated genes immediately return to prepregnancy values 1 day postparturition. Gap junctions and Cx43 expression, for example, decrease rapidly and are undetectable within 24 hr after delivery (6,17). Like Cx43, OTR levels fall shortly after parturition and reach baseline values 1-2 days after parturition (18,22,23). Both COX-1 and COX-2 expression return to preterm levels during involution (19,24), and finally, the concentrations of the excitatory receptors for PGE2 and PGF2, PGE2 receptor (EP2) and PGF2 (FP), respectively, also fall to prepartum levels at 1 day postparturition (25). Moreover, the proliferation of smooth muscle cells and fibroblasts that occurred in early pregnancy decreases as the uterus nears parturition. In late pregnancy and involution of the rat, an increase of apoptosis is seen (26). However, the extent of apoptosis or dedifferentiation that occurs in human myometrial cells during involution is unknown.
During involution, there is an increase of phagocytosis, lysosomal proteins, and matrix metalloproteinases (MMP) in the uterus. Immediately following parturition, smooth muscle cells of the myometrium produce collagenase to degrade the connective tissue fibers formed under the influence of estrogen during pregnancy (27,28). At 2 days postpartum in the rat, mRNA expression of several MMPs is approximately 30-fold higher than that in nonpregnant animals (29). The increase of mRNA expression accompanying increased enzyme activity indicates that rather than storing collagenases in the pro-form, gene transcription in the myometrial cells is signaled at parturition for subsequent collagenase protein (28,29).
Uterine involution does not occur if the increased hormone levels are maintained or if uterine distention is continued after parturition, indicating the significance of both mechanical and hormonal stimuli in uterine involution (20), similar to their combined effects on initiation of parturition. For example, mechanical distention of the uterine wall delays the loss of gap junctions for as long as 2 days postpartum (30). Furthermore, maintenance of increased estrogen concentrations can sustain the concentration of OTR or prevent the activation of MMP-7 and MMP-13 by serotonin (31,32). Given that leiomyomas are hyperresponsive to estrogen either through an increase in estrogen receptor (33-35), an increase in estrogen production (36-38), or dysregulated steroid hormone signaling, the leiomyoma cell may not have the ability to sense an involution-like signal. Thus, the tumors reflect a state of persistent parturition of the pregnant myometrium with inhibited involution under the maintenance of high estrogen levels. The leiomyoma cells are unable to undergo apoptosis or dedifferentiation. Support for this hypothesis has recently been obtained using the Eker rat model for uterine leiomyoma.
To understand the pathogenesis of the human uterine leiomyoma, we have used the Eker animal model. Unlike other animal models in which uterine leiomyomas may be induced by exogenous hormonal stimulation (
39), female Eker rats develop steroid hormone-dependent leiomyomas spontaneously and with a high incidence similar to that of humans. Furthermore, tumors in Eker rats occur when rats are entering reproductive senescence and after prolonged uterine exposure to progesterone and estrogen. Tumors from both Ekers and humans display a typical fusiform pattern, although many Eker tumors are of atypical epithelioid appearance, a relatively rare type found in women (
40). Established cell lines from Eker rat tumors are the first hormonally responsive tumor-derived cell lines for the study of leiomyomas. One such line is the Eker leiomyoma tumor-derived (ELT) cell line, ELT-3, which maintains both estrogen receptor and progesterone receptor responsiveness in culture (
41). This model system provides both
in vivo and
in vitro approaches for manipulation and experimentation.
In vivo and in vitro data obtained with the Eker rat model indicate that leiomyomas do indeed have a defect in their apoptotic program, consistent with the hypothesized defect in parturient signaling. Normal myometrial cells proliferate when steroid hormone levels are at their peak and undergo maximal apoptosis during estrus when steroid hormone levels are at their nadir. Leiomyomas, however, exhibit a marked decrease in the apoptotic fraction of cells relative to age- and stage-matched normal myometrium, and cell lines derived from these tumors fail to undergo apoptosis in vitro when estrogen is withdrawn from the culture medium (42). In addition, changes in the expression pattern of the growth factor and antiapoptotic agent IGF-1 suggest that changes have occurred in the responsiveness of these cells to exogenous estrogen. IGF-1 is expressed in the normal myometrium in response to estrogen. Mature myometrium that is less proliferative than peripubertal myometrium expresses lower levels of this growth factor, suggesting that normal, mature myometrial cells have a decreased responsiveness to circulating estrogen. Leiomyomas arising in aged, reproductively senescent rats that have very low levels of circulating estrogens express abundant IGF-1, suggesting that these tumors may be hypersensitive to low levels of estradiol (43). Human leiomyomas have been shown to overexpress both IGF-1 and IGF-1 receptor (44), indicating they may also have an increased sensitivity to estradiol.
The Eker mutation is maintained on a Long-Evans background and female rats carrying this mutation have a typical gestation of 21 days. Using this animal model, we have analyzed the expression of Cx43, OTR, COX-2, COX-2, and prostaglandins PGE2 and PGF2 in myometrial samples of pregnant animals and in tumors in vivo. Additionally, tumor-derived cell lines are being used to examine the expression and regulation of these key differentiation and parturition factors. Cx43 expression is well documented in human leiomyomas (5), and preliminary evidence suggests that OTR is also expressed in human leiomyomas (32,45). The production of PGE2 and PGF2 in human leiomyomas, however, has not been extensively examined to our knowledge. In the Eker model, we have found Cx43 and OTR to be abundantly expressed in the tumors as well as in the ELT-3 cell line. Moreover, OTR expression is under the control of estrogen. COX-2 expression and subsequent prostaglandin production is downregulated in both the tumors and the tumor-derived cell lines (46).
Leiomyomas may develop because of a number of factors, including dysregulation of gene transcription due to loss or changes of corepressors, coactivators, stabilizers, and other important cofactors that are associated with nuclear hormone receptors, which may result in a hypersensitivity to the sex steroid hormones. For example, Eker rats have an autosomal recessive germline mutation in the tuberous sclerosis-2 (Tsc-2) gene (
47,48). Tuberin, the gene product of this tumor suppressor gene, has recently been suggested to be a cofactor for steroid hormone-mediated transcription (
49), indicating an alteration in this signaling pathway in the Eker animals. The loss of the TSC-2 gene in humans results in the genetic disorder tuberous sclerosis that is characterized by the formation of hamartomas, but loss of TSC-2 has not yet been investigated in human uterine leiomyomas.
In human leiomyomas, members of the high-mobility group (HMG) family of proteins, HMGI-C or HMGI/Y, for example, are commonly overexpressed as a result of structural alterations of the genes. The downstream consequences of this overexpression are not clearly defined (50,51); however, HMG proteins may be involved in estrogen receptor-mediated transcriptional activation (52). HMGI-C is also overexpressed in the Eker leiomyomas. The overexpression of HMGI-C in the Eker model has yet to be demonstrated as a direct genetic alteration, but rather a downstream effect of the loss of TSC-2 function (53). Therefore, despite differences in observed genetic lesions, the behavior of the human and rodent tumors, i.e., responses to steroid hormones and possible aberrant hormone signaling pathways, is quite similar.
In both human and Eker leiomyomas, after tumor cells develop, they persist despite attempts at altering the hormonal milieu. Opportunities for intervention exist in locating and understanding the hormone signaling, differentiation, dedifferentiation, and apoptosis that occur in myometrial cells following parturition and how these pathways may be defective in leiomyomas. We hypothesize that a lack of COX-2 expression and the inability to produce prostaglandins is a major defect in the uterine leiomyoma smooth muscle cells compared to myometrial cells at parturition, which allows the tumor cells to persist. Prostaglandins are involved in the involution of the corpus luteum in rodent models, and several reports link prostaglandins to the initiation of apoptosis in other cell types (54-59). If the complex pathways regulating the expression of the COX enzymes and the production of prostaglandins involved in myometrial involution can be manipulated in the tumor cells to increase cell death or block the cell cycle, effective therapies may be developed as less-invasive alternatives to surgery for the elimination of these tumors.
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Last Updated: October 3, 2000
