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Department of Anatomy (Y.K.H., P.Y., J.F.W., Z.W., G.R.C.) and Department of Growth and Development (P.J.M., R.D.), University of California, San Francisco, California 94143
Address all correspondence and requests for reprints to: Dr. Gerald R. Cunha, Department of Anatomy, Mail Stop 0452, University of California, San Francisco, California 94143. E-mail: grcunha{at}itsa.ucsf.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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7-fold overall) of epithelial LI in response to
estradiol in uterine and vaginal epithelia. These data supported the
hypothesis that overall uterine and vaginal organ growth, in response
to estrogen, required EGFR signaling for DNA synthesis in the
fibromuscular stroma, whereas EGFR signaling was not essential for
estrogen-induced epithelial growth in the uterus and vagina. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, heparin-binding EGF (HB-EGF),
amphiregulin, heregulin, epiregulin, and several other molecules (1, 2), is implicated in uterine and vaginal development, particularly as
mediators of estrogen action. The possible role of the EGF family in
estrogenic effects in the female genital tract is supported by many
studies. Estrogens have effects upon both EGF and EGF receptors in the
uterus (3, 4) and vagina (5) in vivo. Estradiol injected
into immature female rats elicited a 3-fold increase in specific,
high-affinity, saturable binding of 125I-EGF to uterine
membranes (6, 7). After estrogen injection, uterine EGFR binding
increased between 6–12 h, remained elevated at 18 h, and declined
thereafter. This increase in EGFR-binding was blocked by both
cycloheximide and actinomycin D and was specifically induced by
estrogens but not by nonestrogenic hormones (6). A corresponding study,
using ovariectomized rats, showed a 2- to 3-fold elevation of uterine
immunodetectable EGFR 18 h after injection of estradiol (8).
Uterine EGFR transcripts were elevated in ovariectomized rats (9)
within 3 h of estradiol injection, remained elevated at 6 h
after estradiol injection, and then declined thereafter. Estrogenic
effects were blocked by actinomycin D but not by puromycin.
Nonestrogenic hormones did not mimic the estrogen-mediated increase in
EGFR messenger RNA (mRNA) levels. However, for all of the above
studies, it was unclear whether the effect of estradiol on uterine EGFR
reflected changes in the epithelial, stromal, or myometrial
compartments. Nonetheless, these studies suggested that
estrogen-dependent growth of the uterus and vagina were mediated via
EGF ligands acting through the EGFR. Paracrine models of estrogen action in the mouse uterus and vagina were considered for many years because estrogen receptors were expressed in the epithelium, stroma, and myometrial cells (10, 11, 12). Thus, it was possible that estradiol elicited epithelial effects by acting directly upon the epithelium via epithelial estrogen receptors or via estrogen receptors in stromal cells, which in turn, stimulated epithelial proliferation in a paracrine fashion. It was also unknown whether stromal proliferation was regulated by direct or paracrine action of estradiol. It was initially assumed that the myriad effects of estradiol on epithelium were mediated directly through epithelial estrogen receptors. However, analysis of estrogen receptor expression and estradiol responsiveness in the neonatal mouse uterus indicated that this was not correct. Using neonatal Balb/c mice, Cunha et al. (13) demonstrated, with steroid autoradiography, that estrogen receptors were undetectable in uterine epithelium (UtE) but were present in uterine mesenchyme (UtM). Despite the apparent lack of uterine epithelial estrogen receptors in the neonatal mouse, injection of diethylstilbestrol (DES) caused a doubling in the rate of UtE proliferation (14). One explanation for these results could be that DES induced the expression of epithelial estrogen receptors that, in turn, mediated the mitogenic effects of DES on the epithelium. However, Bigsby and Cunha (14) showed that estrogen receptors remained undetectable in the UtE, even after DES stimulation. These results suggested that the mitogenic effects of DES on neonatal UtE could be elicited via paracrine influences from estrogen receptor-positive mesenchymal cells. More recent immunohistochemical studies were consistent with this interpretation (15, 16, 17, 18).
To determine roles of epithelial vs. stromal estrogen receptors in uterine epithelial proliferation, a transgenic estrogen receptor knockout (ERKO) mouse (19) was used to produce uterine tissue recombinants in which epithelium (UtE), stroma (UtS), or both were devoid of functional estrogen receptors. In tissue recombinants prepared with wild-type (WT) uterine stroma (WT-UtS + WT-UtE and WT-UtS + ERKO-UtE), epithelial labeling index (LI) was increased severalfold by estradiol over oil-treated controls (20). In contrast, in tissue recombinants prepared with ERKO uterine stroma (ERKO-UtS + ERKO-UtE and ERKO-UtS + WT-UtE), epithelial LI was low and similar in estradiol- vs. oil-treated specimens. These data clearly demonstrated that estradiol induction of uterine epithelial proliferation was a paracrine event requiring an estrogen receptor-positive stroma. Moreover, epithelial estrogen receptors were neither necessary nor sufficient for estradiol-induced epithelial proliferation. These findings suggested the existence of paracrine mediators of stromal origin, which directly or indirectly regulated epithelial proliferation in estrogen target organs. Growth factors (such as the EGF family of ligands) are likely candidates of such putative paracrine mediators.
To examine the role of EGFR signaling in estrogen-dependent growth of the uterus and vagina, we used a transgenic mouse deficient in EGFR signaling (21), which would be predicted to exhibit impaired uterine and vaginal growth and impaired estrogenic response. These EGFR-KO mice showed growth retardation and epithelial dysfunction, which resulted in gastrointestinal and lung abnormalities resembling human diseases associated with premature birth. EGFR-KO homozygotes displayed epithelial immaturity and multiorgan failure, whereas the heterozygotes developed normally. Some homozygous EGFR-KO embryos died prenatally, but many survived into the early neonatal period before succumbing. Nevertheless, organ rudiments could be rescued from EGFR-KO neonates by grafting them into athymic nude mouse hosts so that estrogenic response could be examined. Using these methods, we investigated the complex interplay between estrogen action, paracrine stromal-epithelial interactions, and EGFR signaling in growth of the uterus and vagina.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Microdissection and tissue recombinations. Female EGFR-KO
mice, normal littermates, and normal female Balb/c mice were killed at
0–3 days postnatal, and entire genital tracts were removed by
dissection. For whole-organ grafts, uteri and vaginae were trimmed as
indicated (Fig. 1
) and grafted under the
renal capsule of female athymic nude mice.
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Histology. The grafts were harvested, fixed in 4% buffered formaldehyde, embedded in paraffin, and sectioned at 6 µm. For histological analysis, specimens were stained with hematoxylin and eosin.
Autoradiography. For analysis of epithelial and stromal LI, paraffin sections of the specimens were mounted on glass slides, dipped in NTB-II photographic emulsion (Kodak, Rochester, NY), and processed autoradiographically via standard protocols (22).
LI. Epithelial LI and stromal LI with 3H-thymidine was determined as the percentage of labeled epithelial or stromal cells in the total population of epithelial or stromal cells, as described previously (22). Individual histological sections to be scored were selected randomly, and for a given section, only regions of appropriate section orientation were scored in which the plane of section was roughly perpendicular to the plane of the epithelial basement membrane. Areas of poor section quality, tangential, or oblique orientation were excluded. For each type of graft, a minimum of 300 cells were scored per individual specimen for 3–6 replicate specimens.
Statistics. Values were expressed as the mean ± SEM of at least six different experiments. Differences among means were estimated using a Student’s unpaired t test and ANOVA. Differences were considered significant at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Although grafts of EGFR-KO uteri
were somewhat smaller than WT grafts after 1 month of growth,
development of both epithelium and mesenchyme was normal and was
equivalent to that of grafts of WT uteri (Fig. 2, a and b).
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, c and d).
Stromal cells in grafted uteri and vaginae from EGFR-KO mice had an
impaired proliferative response to estradiol. We found that
overall growth (wet weight) was reduced in grafts of EGFR-KO
vs. WT uteri and vaginae. To explain this difference in size
of EGFR-KO uterine and vaginal grafts, we determined cell proliferation
by analyzing incorporation of 3H-thymidine and stromal cell
LI’s in grafts of intact WT and EGFR-KO uteri. LI for uterine stromal
cells of EGFR-KO uteri in response to estradiol was indistinguishable
from that of oil-treated controls (Fig. 3A). This contrasts with an increase in
stromal cell LI of WT uterine grafts treated with estradiol, which was
4.6 times higher than that of WT uteri treated with oil and 2.3 times
higher than that of its EGFR-KO counterpart. Similarly, in
estradiol-treated EGFR-KO vaginal grafts, stromal cell LI was
indistinguishable from that of its oil-treated counterpart (Fig. 3B).
In contrast, in estradiol-treated WT vaginal grafts, stromal cell LI
was 19.5 times higher than that of its estradiol-treated EGFR-KO
counterpart and 6.4 times higher than its WT oil-treated counterpart.
These data indicated that stromal response to estradiol was markedly
impaired in EGFR-KO mice.
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, UtE of both
EGFR-KO and WT uterine grafts responded comparably to estradiol by
incorporation of 3H-thymidine. Epithelial LI in WT uterine
grafts increased approximately 4-fold in response to estradiol,
relative to WT uterine grafts treated with oil. Epithelial LI in
EGFR-KO uterine grafts treated with estradiol increased approximately 9
times, relative to that of EGFR-KO uterine grafts treated with oil.
Epithelial LI’s for WT and EGFR-KO uterine grafts treated with oil
were not significantly different from each other at P
< 0.05.
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). Epithelial LI’s in WT vaginal grafts treated with
estradiol were elevated approximately 3-fold, relative to epithelial LI
of WT vaginal grafts treated with oil. Similarly, EGFR-KO vaginal
grafts treated with estradiol exhibited an increase in epithelial LI
approximately 11 times higher than that of EGFR-KO vaginal grafts
treated with oil. Epithelial LI’s for WT and EGFR-KO vaginal grafts
treated with oil were not significantly different from each other at
P < 0.05. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, histological analysis of uterine and vaginal grafts
indicated that their epithelia grew and differentiated normally when
grafted into intact female nude mouse hosts. Our group routinely
grafted embryonic and neonatal organs from both male and female
rodents. These renal capsule grafts displayed normal growth,
morphogenesis, and differentiation. Moreover, markers of adult function
were expressed by grafts of embryonic or neonatal organ rudiments
usually by 3–4 weeks after grafting. For example, lactotransferrin was
expressed by neonatal uterine grafts or homotypic neonatal uterine
tissue recombinants (UtM + UtE) grown for 4 weeks in adult female hosts
(20). For this reason, it was important to recognize that our
experimental model did not relate to hormonal response of neonatal
organs but instead, more appropriately, to postnatal organs at on
advanced stage of functional differentiation comparable, in many ways,
to adult organs. The EGFR-KO mouse was described to undergo multiorgan failure (21), which led to its demise in the early neonatal period. Given the short life span of the EGFR-KO mouse, it was not possible to determine whether congenital abnormalities were reversible with time. Moreover, in the original description of the EGFR-KO mouse (21), only a limited number of organs were examined. Given this background it was striking that uterine and vaginal development was so normal in uterine and vaginal grafts from EGFR-KO neonatal mice. Perhaps the effects of EGFR-KO were variable in different organs. Alternatively, developmental abnormalities that existed during development of EGFR-KO uteri and vaginae were not observed at the end of our experiments because, given the extended period of growth in the nude mouse hosts, such abnormalities could be repaired through compensatory mechanisms. In any case, it should be emphasized that the embryonic and early neonatal development of the female Müllerian ducts and the urogenital sinus was normal in EGFR-KO mice. For this reason, the neonatal female genital tract of the EGFR-KO mouse was slightly smaller than, but otherwise indistinguishable from, the WT.
Many of the organs that were adversely affected in the EGFR-KO mouse were composed of epithelium and mesenchyme. In the present study, we found that the uterus and vagina of EGFR-KO mice exhibited a generalized growth deficit of 34–38%. Although EGFR signaling was absent simultaneously in both epithelium and mesenchyme in EGFR-KO mice, our data suggested that the lack of functional EGFR in uterine and vaginal stroma was the key event accounting for overall organ hypoplasia in the female genital tract and impaired overall growth of EGFR-KO vs. WT uteri and vaginae. Tritiated-thymidine LI studies supported this conclusion. It should be recognized that 3H-thymidine incorporation did not differentiate DNA replication from DNA repair. However, all controls and experimental conditions reported in this study behaved normally with respect to known proliferative (DNA synthetic) response to estradiol. LIs of the stroma of EGFR-KO uterine and vaginal grafts treated with estradiol demonstrated a complete absence of proliferative response to estradiol. The growth deficiency of the EGFR-KO uterus and vagina could also be caused by a higher rate of apoptosis, although this was not measured in this study. Estradiol is known to inhibit apoptosis in granulosa cells of the rat ovarian follicle, and the lack of EGFR signaling here could inhibit estrogen-induced apoptosis. In any case, EGFR signaling seems to be required for optimal estrogen-dependent stromal growth in the uterus and vagina. Because the epithelium forms only about 10%, whereas the fibromuscular wall forms about 90% of the uterus (23), impaired growth of the stroma more profoundly affected overall organ size than impaired growth of the epithelium, which only constituted a small fraction of the uterus. Our results were consistent with a model in which the estrogen-receptor-mediated action of estradiol in either the epithelium or stroma elicited production of EGF ligands that subsequently interacted with the EGFR on stromal cells and stimulated stromal proliferation. The impaired stromal DNA synthesis in EGFR-KO mice indicated that estradiol by itself was not a complete mitogen for uterine or vaginal stromal cells, but instead that EGF ligands produced by the stromal cells and acting in an autocrine manner, or EGF ligands produced by the epithelium and acting as a paracrine manner, were involved in estrogen-induced growth of uterine and vaginal stromal cells.
Parallel studies in estrogen receptor-deficient (ERKO)/WT tissue
recombinants clearly demonstrated that estradiol induction of uterine
epithelial proliferation was a paracrine event requiring estrogen
receptor-positive stroma (20). The current study extended these
observations using EGFR-KO uteri and vaginae. We found that
estrogen-induced epithelial growth mediated by stromal estrogen
receptors was normal, suggesting that estrogen-induced
stroma-mediated epithelial growth did not require the EGFR signaling
pathway in the epithelial cells. Furthermore, the results of this study
indicated that a functional stromal EGFR pathway was not required for
stromal production of estrogen-induced paracrine factors necessary for
epithelial cell growth but could be more crucial for uterine and
vaginal stromal growth. It was reported that the preimplantation uterus
differentially expressed full-length (EGFR-fl) and a truncated
(EGFR-tr) forms of the EGFR (24). The EGFR-fl is a fully functional
receptor, whereas the EGFR-tr is a secreted protein, which is not
thought to have any direct cell signaling capabilities. In
situ hybridization studies indicated that EGFR-fl transcripts were
found only in the uterine stroma and myometrium, but not in the
epithelium, whereas EGFR-tr message was detected in all major uterine
cell-types (24). These findings were corroborated by
immunohistochemical results showing that EGFR was detected only in the
uterine stroma, deciduum, and myometrium, but not in the uterine
luminal or glandular epithelium of the early pregnant mouse (25).
Additionally, EGF ligands were shown to bind to a variety of other
erb-B receptors (26). Using in situ hybridization, erb-B2
mRNA was detected primarily in uterine epithelial cells on days 1–4 of
pregnancy in the mouse with the highest level found on day 1 (27).
Further analysis showed that ovariectomized mice, treated with
estradiol, up-regulated erb-B2 expression in the UtE by 3.5-fold using
a combination of RT-PCR and in situ hybridization (27).
Thus, it was possible that in EGFR-KO mice, EGF ligands could still be
important for uterine/vaginal epithelial growth by signaling through
these other receptors. Given the complexity of the EGF ligand family,
it was not surprising that deletion of a single growth factor gene,
such as TGF, did not compromise the health or fertility of TGF-KO
mice (28). Taken together, these data imply that UtE was not the direct
target for the effects of EGF-type growth factors and that their
mitogenic effects were actually mediated by paracrine mechanisms
involving other uterine cell-types expressing EGFR. Arguing against
this interpretation are in vitro studies that showed a
direct effect of EGF upon isolated UtE (29, 30). Using a collagen gel
culture system, dissociated uterine and vaginal epithelial cells
responded to EGF with growth in a serum-free, defined culture medium
(29, 30). Unlike the in vivo situation, however, estradiol
did not stimulate growth for vaginal or uterine epithelial cells in a
similar collagen gel culture system (31), so comparisons between
in vitro and in vivo results were difficult to
reconcile. In any case, we could not rule out the possibility that, in
WT mice, EGFR signaling in the epithelium occurred and was involved in
estrogen-induced uterine and vaginal epithelial proliferation in
vivo. However, in EGFR-KO mice, other ligand-receptor systems
could clearly compensate for the lack of EGFR in the epithelium. One
such possibility was erb-B2, which is a receptor subtype, capable of
binding EGF-related ligands in uterine epithelial cell
proliferation (27).
Several EGF ligands are produced in the uterus and vagina.
Uterine and vaginal epithelial cells were stimulated by estradiol to
produce EGF and/or TGF (5, 32). However, in the uterus, EGF seemed
to be secreted apically into the uterine lumen (32) and, thus, could
not be available for interaction with EGFR in either stromal or
epithelial cells. Similarly, vaginal epithelium (stimulated in
vivo by estradiol) expressed TGF transcripts in suprabasal cell
layers (33), which again raised the possibility that EGF ligands
produced by vaginal epithelium could be unavailable for interaction
with stromal or epithelial EGFR. TGF expression also was found in
the mouse uterus during the periimplantation period (day 1–4 of
pregnancy) in a cell-type specific manner (34, 35). By in
situ hybridization and immunoblot analysis, TGF (34) and
proTGF (35), respectively, were localized in the luminal and
glandular epithelia on days 1–4 of pregnancy, and many of the stromal
cells expressed TGF on days 3–4 of pregnancy. In the uterus of
ovariectomized adult rats, the production of HB-EGF was stimulated in
uterine stromal cells by progesterone (P) or P followed by estradiol.
Such hormonal treatments repressed HB-EGF expression in the UtE,
whereas estradiol alone increased HB-EGF expression in the epithelium.
For ovariectomized adult mice, coinjection of P plus estradiol
stimulated HB-EGF expression in uterine stromal cells, as detected by
in situ hybridization, whereas estradiol alone increased
expression of HB-EGF only in the epithelium (36, 37). Amphiregulin was
induced by P in the uterine luminal epithelium of ovariectomized mice
(38), whereas TGF expression was stimulated by DES in the uterine
epithelial cells, with only a modest increase in TGF expression in
uterine stromal cells (32). Thus, EGF ligands were produced by both
epithelial and stromal cells, and therefore, proliferation of uterine
and vaginal stromal cells could be elicited via either autocrine or
paracrine mechanisms.
Thus, our results (using an EGFR null mutant mouse) showed that EGFR signaling was required for estrogen-induced proliferation of uterine and vaginal stromal cells but challenged the generally accepted notion that the EGFR receptor signaling system was crucial for estrogen-induced proliferation of uterine and vaginal epithelial cells.
If EGFR were not needed for estrogen-induced epithelial growth, then some other signaling pathway(s) in the uterus and vagina was used to elicit epithelial mitogenesis mediated via estrogen receptors in the stroma. Of the many possible compensatory growth factor pathways which could play key roles in estradiol-induced epithelial growth, keratinocyte growth factor (KGF), HGF, and insulin-like growth factor 1 (IGF-1) were worthy of consideration.
KGF fits many of the criteria considered essential for a mesenchymal mediator of epithelial development. Uterine tissue from cycling and ovariectomized monkeys, treated with combinations of estradiol and P, expressed KGF mRNA, which was increased in animals in the luteal phase or in animals treated with P (39). Thus, KGF was suggested to be a P-induced, stromally-derived, progestomedin. We found that KGF, injected directly into newborn female mice, stimulated uterine epithelial growth (unpublished results). However, KGF was highly induced after incisional wounding of the skin (40, 41, 42) and the bladder (43). Thus, it was perhaps worth considering whether the apparent induction of KGF in the uterus by P was secondary to apoptotic damage associated with reduced estrogen levels in the luteal phase. In any case, KGF could be an important paracrine mediator for uterine epithelial growth.
Hepatocyte growth factor (HGF, scatter factor) is mitogenic for epithelial cells of a number of estrogen-sensitive organs, including the mammary gland (44, 45, 46) and uterus (45). HGF transcripts were detected by RT-PCR in the adult mouse uterus, and c-met mRNA expressed in the UtE by in situ hybridization (45). HGF expressed in mammary stromal cells, stimulated ductal branching, and inhibited production of secretory proteins in organ culture (45). Proliferation of primary mouse mammary epithelial cells was stimulated by coculture with primary mouse mammary fibroblasts that produced HGF (44). Thus, HGF is another potential mediator of stromal effects on epithelial growth in the female genital tract.
IGF-1 also has been suggested to be a mediator of estrogen-stimulated proliferation in the uterus. IGF-1 and IGF-1 receptor expression were up-regulated in response to estrogen (47, 48, 49). Immature rats, implanted sc with pellets containing estradiol, exhibited an elevation in uterine IGF-1 and IGF-1 receptor mRNA after 72 h of treatment (50). Transgenic mice (homozygous for a null mutation of the IGF-1 gene) had thin, flaccid uteri with a wet weight only 13% that of WT mice (51). Another transgenic mouse, overexpressing IGF-binding protein-1 showed a significant reduction in both estradiol- and IGF-1-induced uterine DNA synthesis, compared with WT mice (52). IGF-1 expression was found in the uterine glandular and luminal epithelial cells on days 1–2 of pregnancy, whereas stromal cells, on days 3–4 of pregnancy and decidual cells on days 5–6 of pregnancy seemed to be the predominant sites of IGF-1 production (53). Treatment of ovariectomized mice with P and/or estradiol induced IGF-1 expression. Estradiol specifically induced IGF-1 in uterine epithelial cells, whereas P induced IGF-1 in stromal cells (53). The combination of both estradiol and P further stimulated IGF-1 expression in the uterine stroma. Taken together, these studies suggested that KGF, HGF, and IGF-1 were important for estradiol-induced epithelial growth and that they could compensate for KO of the EGFR signaling pathway.
We conclude that EGFR signaling was required for estrogen-induced uterine and vaginal stromal growth but not for estrogen-induced growth of uterine or vaginal epithelium. The resulting impaired stromal growth in EGFR-KO mice led to overall organ hypoplasia. Given the more extensive contribution of mesenchyme to the overall mass of the uterus, and the fact that uterine and vaginal mesenchyme played a central role as an inducer of uterine and vaginal development (54), the absence of EGFR signaling in the mesenchyme of EGFR-KO mice seemed to account, in large part, for the generalized hypoplasia of estrogen-sensitive female genital tract organs. Although EGFR signaling could be used during estrogen-induced uterine and vaginal epithelial proliferation in vivo in wild-type mice, other, more important growth factor systems could act in conjunction with EGF to elicit epithelial growth. Clearly, other ligand-receptor systems did compensate for the lack of EGFR function in estrogen-induced proliferation of uterine and vaginal epithelia.
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Footnotes |
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Received August 13, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T. Kurita, P. Young, J. R. Brody, J. P. Lydon, B. W. O'Malley, and G. R. Cunha Stromal Progesterone Receptors Mediate the Inhibitory Effects of Progesterone on Estrogen-Induced Uterine Epithelial Cell Deoxyribonucleic Acid Synthesis Endocrinology, November 1, 1998; 139(11): 4708 - 4713. [Abstract] [Full Text] [PDF]
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R. B. Roberts, L. Min, M. K. Washington, S. J. Olsen, S. H. Settle, R. J. Coffey, and D. W. Threadgill Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis PNAS, February 5, 2002; 99(3): 1521 - 1526. [Abstract] [Full Text] [PDF]
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