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Department of Urology (W.Y.C., L.B., G.S.P.), University of Illinois, Chicago, Illinois 60612; Department of Urology (H.H.), University of Graz, Austria; and Department of Medicine and Sylvester Comprehensive Cancer Center (P.M.), University of Miami School of Medicine, Florida 33136
Address all correspondence and requests for reprints to: Gail S. Prins, Ph.D., Department of Urology, University of Illinois at Chicago, M/C 955, Chicago, Illinois 60612. E-mail: gprins{at}uic.edu
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(ER) and estrogen
receptor ß (ERß). In the normal developing prostate, ER
expression is confined to periductal mesenchymal cells surrounding the
proximal ducts, whereas ERß is expressed at low levels in the
undifferentiated epithelial cells (8, 9). Although
neonatal exposure to estrogens does not initially alter ERß
expression (9), there is an immediate up-regulation
of ER expression within periductal stromal cells along the length of
the developing ducts that allows for amplification of estrogenic
signals in these stromal cells at the time of neonatal exposure
(8). We have previously shown that neonatal estrogen
exposure initially blocks prostatic epithelial cells from entering a
normal differentiation pathway as characterized by a lack of
p21cip-1/waf-1, a delay in the appearance of
luminal cell markers, a retention of a continuous layer of basal cells
along the basement membrane, and loss of androgen receptor (AR)
(10, 11). Differentiation defects of the epithelium can be
permanent as evidenced by reduced adult expression of epithelial ERß
and decreased expression of several secretory proteins including
prostate binding protein (PBP), urokinase and a 21-kDa secretory
protein (4, 9, 10, 12). In addition, we have recently
shown that neonatal estrogens stimulate the proliferation of a zone of
fibroblasts beneath the basement membrane that may impede ductal
branching and cell-cell interactions between smooth muscle and
epithelial cells (12).
Cell junctions, particularly abundant in epithelial cells, are
macromolecular structures that are essential for intercellular adhesion
and communication. Signal transduction through cell junction-associated
adhesion molecules has been implicated in the control of proliferation
and differentiation of epithelial cells during normal and neoplastic
development (13). The membrane channels of gap junction
(GJ)s, formed of proteins called connexin(Cx)s, provide an
intercellular pathway for the diffusion of small growth-regulatory
molecules (
1 kD) between the cytoplasmic interiors of contigous cells
(14), a process commonly referred to as gap junctional
intercellular communication (GJIC) (15, 16). The presence
of GJs in most tissues at early embryonic development and the recent
demonstration of mutations in Cx genes in certain human genetic
disorders point to crucial biological roles of GJIC (14).
The cell-to-cell channels are bicellular structures formed by members
of the Cx family of related proteins that first are assembled into
hexamers to form connexons that align and join with connexons in
adjacent cells to form intercellular pathways (17).
Currently, 16 distinct Cx genes, which are designated according to
their molecular mass, have been cloned (18). Although all
Cxs share a similar topology, some Cxs are expressed in a
tissue-specific manner, form channels of different permeabilities, and
show specificity in docking to other Cxs (14). While GJIC
has been long postulated to fulfill the roles of intercellular
buffering of cytoplasmic ions and synchronization of cellular behavior,
direct evidence for these roles has only recently been obtained from
gene knockout studies (14). In addition to well-documented
role of GJIC in the maintenance of tissue homeostasis and cellular
behavior, evidence is mounting that bidirectional signaling between
cell adhesion molecules, such as E-cadherin, and Cxs may be crucial for
controlling embryonic development (19, 20).
The ability of cells to form GJs with some cells and not with others enables the formation of "communication compartments" that may allow the restriction of morphogens to appropriate developmental regions (15, 21). Because GJIC has been shown to be modulated by a variety of agents—such as growth factors, hormones, and oncogenes—it is possible that these agents affect cell growth, differentiation, and tissue homeostasis by modulating the expression and function of Cxs. The spatio-temporal expression of several Cx genes during embryonic development and organogenesis is well established (21, 22). In the limb bud, for example, GJs are found between epithelial cells as well as between mesenchymal cells where they are distributed in the form of a gradient (23). Presently, there are no reports on connexin expression and patterning in the developing prostate gland. In the adult rat prostate, as in other exocrine glands, Cx32 and Cx26 have been found on secretory epithelial cells, whereas Cx43 was not observed (24). Reports on connexin expression in normal adult human prostate are controversial. While some investigators found Cx32 and no Cx43 expression (25, 26), others reported the presence of Cx43 in benign prostate cells (27). It is significant to note that GJ-protein expression is regulated, in part, by steroid hormones in steroid sensitive organs. Importantly, Cx43 messenger RNA levels are up-regulated by estrogens in myometrial cells (28). Labor and estrogens increase Cx43 in rat myometrium while progesterone suppresses Cx43 expression (29) via increased c-fos messenger RNA (30). Additionally, testosterone has been shown to increase Cx32 expression in spinal cord motorneurons (16).
For GJ to form, the members of the interacting cells must be close to one another and cell adhesion molecules (CAMs) seem to be involved in this coupling process (31) and in regulating connexin expression (19, 20, 32). Vice versa, the formation of adherens junctions is impaired if GJIC is blocked (18). CAMs are transmembrane proteins that bind in a homophilic manner and form belt-like cell-cell adhesion. CAMs are grouped into two categories: the cadherins, the cell adhesive properties of which are Ca2+-dependent, and the immunoglobulin superfamily CAMs. Among the cadherins, E(epithelial)-cadherin is expressed first on all early mammalian embryonic cells and is later restricted to epithelial tissues of embryos and adults (33, 34). Cadherins transmit intercellular signals through catenin proteins that connect the cytoplasmic region of the cadherins to the cytoskeleton of the cell. Cadherins are extremely important in establishing and maintaining cell-cell interactions between epithelial cells and in adults, are critical for retaining epithelial integrity (34).
In adult cells, loss of E-cadherin is associated with malignancy (35, 36). Likewise, the majority of neoplastic cells have fewer GJ and GJIC is impaired compared with non-neoplastic cells (16). In prostate carcinoma cells, a decrease in Cx43 expression has been reported compared with benign prostate cells and eventual loss of both connexins 32 and 43 occurs in advanced carcinoma (25, 27). Restoration of connexin gene expression and GJIC in vitro and in vivo by gene therapy can reduce tumor cell growth (36, 37). Similarly, reconstitution of an epithelial-specific CAM (C-CAM) via gene therapy was found to repress tumor growth in prostate cancer in vitro and in vivo (38).
Since cell-cell communication through gap junction proteins and E-cadherins are critical for normal development, since their expression can be regulated by steroids and since aberrant expression is associated with dysplasia and tumor formation, we were interested in the present study in determining 1) the ontogeny of connexins and E-cadherin expression in the rat prostate; 2) whether neonatal estrogens could influence their developmental expression; and 3) whether changes in connexin and E-cadherin in estrogenized prostate glands were associated with epithelial hyperplasia and dysplasia in the adult. To accomplish these objectives, developing and adult prostates of control and estrogenized rats were studied by immunocytochemistry using specific antibodies against connexins, E-cadherin and a variety of cell markers in the prostate gland.
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Materials and Methods |
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Immunocytochemistry
Immunocytochemistry was performed according to previously
published methods (39). Briefly, frozen prostatic
complexes or individual lobes were mounted on precooled chucks (-20 C)
in a Reichert-Jung cryostat and sections (6 µm) were thaw-mounted on
gelatin-coated glass slides. Whenever possible, individual lobes were
sectioned longitudinally to reveal the proximal-distal orientation. At
4 C, the sections were fixed in 2% paraformaldehyde, rinsed, incubated
with appropriate 2% blocking serum (goat or horse) and incubated
overnight with primary antibody. The specific antibodies, sources and
concentrations used are presented in Table 1
. As a negative control, normal rabbit
(Vector Laboratories, Inc., Burlingame, CA) or mouse IgGs
(Zymed Laboratories, Inc., South San Francisco, CA) at 1
µg/ml were substituted for primary antibody on separate sections of
all tissues analyzed to determine nonspecific binding. The primary
antibody was reacted with biotinylated antigoat or antihorse IgG
secondary antibody (Vector Laboratories, Inc.), and
detected with an avidin-biotin peroxidase kit (ABC-Elite, Vector Laboratories, Inc.) using diaminobenzidine tetrachloride as a
chromagen. The sections were stained with Gill’s no. 3 hematoxylin
(1:4) as a blue nuclear counterstain. As a final step, the sections
were dehydrated gradually with alcohol, cleared with xylene, and
coverslipped with Permount (Fisher Scientific, Inc.,
Itasca, IL).
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Photographs of diaminobenzidine tetrachloride stained slides were taken with an Olympus Corp. BHTU microscope system (Olympus Corp., New Hyde Park, NY) using Kodak Ektachrome Elite 100 film (Eastman Kodak Co., Rochester, NY).
Colocalization with fluorescence-immunocytochemistry
The protocol used was similar to that for immunocytochemistry.
After overnight incubation with the first primary antibody, the tissue
section was incubated with fluorescein-conjugated anti-mouse or
antirabbit secondary antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) for 1 h at 37 C. After
washing with PBS/gelatin and incubating with appropriate 2% blocking
serum (donkey or goat) at room temperature, sections were incubated
with the second primary antibody for 1 h at 37 C (or for actin,
overnight at 4 C). Tissues were then incubated with CY3-conjugated
anti-rabbit or anti-mouse secondary antibody for 1 h at 37 C and
washed with deionized water. Coverslips were mounted with Vectashield
containing DAPI (Vector Laboratories, Inc.) to visualize
nuclei. Photographs of the fluorochrome-labeled slides were taken using
a Carl Zeiss Axioscope (Carl Zeiss, New York,
NY) and a Princeton Instruments Microview digital camera
(Princeton Instruments, Trenton, NJ). For comparative
studies, tissues from different time points as well as from control and
estrogenized rats were always run in parallel to reduce discrepancies
related to interassay variability in staining intensity. In most
instances, photographs comparing treatments and days were taken from
tissues processed on the same glass slide. Ventral, dorsal and lateral
lobes from 3–6 animals at each time point were evaluated to ensure the
reproducibility of results.
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Results |
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). In addition, urogenital sinus (UGS)
mesenchymal cells also expressed Cx43 abundantly; however, the
immunostaining was confined to periurethral mesenchyme and did not
extend through the smooth muscle sleeve into the prostatic mesenchyme
(Fig. 1, B and C). Over the course of the first 10 days of life, while
Cx43 expression in UGS mesenchyme declined to an undetectable level, a
gradient of Cx43-specific immunostaining was observed in the developing
epithelial ducts whose intensity was the strongest at the distal tips
of the buds that had not luminized yet. When the epithelial ducts began
to luminize between days 10–15, Cx43 expression was confined to
basally positioned cells at the periphery of the ducts, whereas in the
luminal cells it was absent (Fig. 1D). The number of Cx43-expressing
epithelial cells continued to decline through maturation of the gland.
Concomitant with the loss of Cx43 immunostaining in the developing
prostate was the appearance of punctate Cx32 immunostaining in
epithelial cells along the lateral surfaces of differentiated luminal
cells, observed first at day 15 and increasing in intensity at day 30
(Fig. 1E) and 90 (Fig. 1F). To characterize further the pattern of
expression of Cxs in the basal and luminal cells of rat prostate, we
studied the colocalization of Cx43 and Cx32 with each other and with
specific cell markers. Cx43 and Cx32 did not localize to the same cells
but rather were confined to distinct epithelial cell populations. At
day 15, the majority of epithelial cells expressed Cx43, whereas by day
30, the number of cells expressing Cx 43 had declined and there was an
apparent increase in the proportion of cells expressing Cx 32. By day
90, the major fraction of prostatic epithelial cells were Cx32
positive, whereas only a minor fraction of cells were Cx43 positive.
This shift in Cx43 and Cx32 expressing cells coincided with the known
time frame of epithelial cell differentiation in the prostate from
undifferentiated basal cells (days 1–10) to bilayers of basal and
luminal cells (days 10–15) to a vast majority of luminal cells (adult
tissue) (10). Thus we colocalized the connexins with
specific cell markers for basal and luminal epithelial cells. At day 6
and 10, Cx43 colocalized with cytokeratins 5/15, which are markers of
basal epithelial cells (Fig. 2A). In day
90 prostates, Cx32 colocalized to cells containing cytokeratins 8/18
(Fig. 2B), which are markers of differentiated luminal cells. Of
interest, a sparse number of basally located cells were not stained by
either antibody. These data confirm that Cx43 is the gap junction
protein in prostatic basal cells whereas Cx32 is the gap junction
protein of differentiated luminal cells.
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-actin
as a marker for differentiated smooth muscle cells. Because -actin
first appears in the developing ventral prostate around day 3
(10), we examined days 4, 5, 6, and 10 for Cx43 and
-actin and days 15 and 30 for Cx32 and -actin. At days 4–6, Cx43
primarily localized to periurethral mesenchymal cells that did not
stain for -actin (Fig. 2
, C and D). Differentiating periductal
smooth muscle cells in the proximal regions of the prostate colocalized
with Cx43; however, this did not extend past the smooth muscle sleeve
surrounding the UGS. At day 15, a small number of periductal smooth
muscle cells colocalized -actin and Cx32, however, this disappeared
by day 30 (Fig. 2, E and F).
2) Ontogeny of E-cadherin in rat prostate
Undifferentiated epithelial cells of the developing prostate gland
stained positive for E-cadherin at cell-cell contact areas (Fig. 3A). The staining
intensity markedly increased between days 10–15 when epithelial cells
of the ventral, dorsal and lateral lobes began to differentiate into a
luminal cell phenotype. Luminal cell staining increased further between
days 15–30 as the majority of epithelial cells became functionally
differentiated (Fig. 3B). In the adult day 90 rat prostate lobes,
intense staining for E-cadherin was found along the lateral borders of
all luminal epithelial cells, and this expression continued in the aged
(16 months) prostates where intense staining was observed in both
cuboidal and columnar epithelial cells (Fig. 3C). Colocalization
studies in the day 90 prostate revealed that Cx32 and E-cadherin
colocalized to the same luminal epithelial cells but not always to the
same spots on the cell membrane (Fig. 3D).
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) in contrast to the
distinct membrane localization of control ventral lobes (Fig. 2F). Our
previous studies have found that neonatal estrogen has lobe-specific
effects on the adult prostate (40). While all lobes show a
growth inhibition in response to early estrogen exposure, epithelial
hyperplasia and dysplasia are most prominent in the ventral prostate
with moderate effects observed in the dorsal lobe. In contrast, the
lateral lobes do not exhibit epithelial distortion and dysplasia with
aging following a brief exposure to estrogens during the neonatal
period. To determine whether the epithelial differentiation defects and
development of dysplasia were associated with alterations in Cx 32, Cx
43, and E-cadherin levels, we focused on the ventral prostate lobes of
young adult and aging ventral prostates in the present study. Adult
ventral prostates of neonatally estrogenized rats exhibited a marked
decrease in Cx32 staining (Fig. 4, B and E) compared with oil-treated
controls (Fig. 1F). At the same time, there was an increased proportion
of Cx43 expressing cells in the adult ventral prostate lobes (Fig. 4C)
in contrast to the infrequent Cx43 positive cells in control prostates
(Fig. 4D). The observed higher number of Cx43-expressing basal cells
were most noticeable in the proximal and central regions of the
estrogenized ducts upon examination of longitudinal sections. This
shift in connexin protein profiles in prostate epithelia corresponds to
the known accumulation of undifferentiated basal-type cells in response
to neonatal estrogen exposure (10). However, a change in
the proportions of epithelial cell types does not alone explain the
alterations in connexin profiles in the estrogenized prostates.
Colocalization of Cx32 and cytokeratin 8/18 (luminal cell marker) in
estrogenized prostates revealed a decrease of Cx32 expression in
luminal cells compared with controls (Fig. 4E), particularly in
hyperplastic areas (Fig. 4F), whereas there was a complete loss of Cx32
in dysplastic epithelia.
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), estrogenized prostates contained Cx43-expressing cells
into the proximal regions of the ventral prostate mesenchymal pad
(i.e. beyond the smooth muscle sleeve). Colocalization of
Cx43 with -actin revealed that this proximal Cx43 staining
primarily localized to actin-negative, periductal fibroblasts (Fig. 4H)
and only occasionally to differentiating smooth muscle cells.
Colocalization studies of Cx32 and -actin showed no expression of
Cx32 in smooth muscle cells of the day 15 and 30 estrogenized prostates
and instead occasional Cx32 staining in fibroblast cells (Fig. 4A).
E-cadherin immunostaining was present but less intense in the
undifferentiated epithelial cells of day 6–10 estrogenized prostates
when compared with oil-treated controls (Fig. 3E). As epithelial cells
in the central to distal regions of the gland differentiated between
days 15–30, strong E-cadherin stain was observed similar to
control tissues. However, as early as day 30, small foci of epithelial
cells which were E-cadherin negative, were noticeable within the ducts
of estrogenized ventral prostates (Fig. 3F). In day 90 and 16-month-old
ventral prostates, larger foci with differentiation defects and
dysplasia were associated with loss or decrease in E-cadherin
immunostaining in the epithelium (Fig. 3G). Colocalization of
E-cadherin with Cx32 revealed that in normal appearing regions of
neonatally estrogenized adult prostates both Cx32 and E-cadherin were
reduced (Fig. 3H), whereas dysplastic glands expressed no Cx32 and only
very low E-cadherin.
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Discussion |
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Mesenchymal cells of the UGS and basal cells of the developing prostate ducts expressed Cx43 during the same period (day 1-day 15). Mesenchymal Cx43-expression was strong at birth in periurethral mesenchymal cells and did not extend past the smooth muscle sleeve surrounding the UGS into the prostate proper in normal control rats. As the process of morphogenesis continued, Cx43 expression in periurethral stromal cells was lost suggesting that it is only expressed in a subset of undifferentiated mesenchymal cells. In turn, Cx32 was observed in differentiated smooth muscle cells for a limited period of time during morphogenesis. In those cells, Cx32 expression was highest at day 15, declined markedly by day 30 and was not found in the adult prostate smooth muscle cells. These findings suggest that mesenchymal and stromal cells communicate through these specific gap junctions during the period of morphogenesis only. While reports on connexin expression in mesenchymal cells are limited, both Cx43 and Cx32 have been identified in mesenchymal cells of fetal chicks and mice (42, 43). Interestingly, in the developing chick limb buds, high Cx43 expression in the ectodermal ridge has been shown to induce gap junction expression in distal mesenchymal cells (34).
For both epithelial and mesenchymal cells, the "switch" from Cx43 to Cx32 expression appears to be associated with differentiation. Developmental "switches" in the expression of GJ-protein subclasses are reported in other cell systems and are associated with maturation processes (44, 45). GJIC is believed to provide a mechanism for coordination of cellular activities in "developmental compartments." The down-regulation of a particular connexin may reflect an early change in metabolic activity within a certain compartment associated with subsequent quiescence of these cells (14). In this sense, the decreased expression of Cx43 may reflect a decreased metabolic activity of the basal and mesenchymal cell population, whereas the increase in Cx32-expression with age could be an expression of increased activity in the luminal cell compartment and a transient increased activity in differentiated smooth muscle cells.
Developmental estrogenization
Following neonatal exposure to estradiol, there were no immediate
alterations noted in Cx43 immunostaining in undifferentiated basal
cells. Similarly, when epithelial cells began to show evidence of
differentiation into luminal epithelial cells, albeit at a delayed
rate, Cx32 immunostaining was present in those cells. The first
observed difference in epithelial connexin expression noted in
estrogenized prostates was at day 30 when Cx32 was localized within the
cytoplasm in contrast to the distinct membrane-associated localization
observed in control prostates. Similar alterations in Cx32
redistribution to the cytoplasm from the membrane have been reported
for human prostate cancers (25). Interestingly, in
moderately differentiated carcinomas, Cx32 immunostaining was
frequently localized to the cytoplasm, whereas in poorly differentiated
cancers, there was loss of Cx32 expression altogether. It has been
noted that neoplastic cells have fewer GJ compared with homologous
nonneoplastic cells and reduced GJIC compared with their normal
counterparts (16). Likewise, the restoration of GJIC in
neoplastic cells by means of overexpression of connexin genes has
resulted in abrogation of neoplastic growth and tumorigenicity
(16, 25, 46). In the present study, aging of the
estrogenized rat prostates resulted in a decrease in Cx32 expression in
the luminal epithelial cells of the ventral lobe, which was most
pronounced in areas of hyperplasic and dysplastic epithelium. The cause
of reduced Cx32 expression may relate to the loss of androgen receptor
expression in permanently imprinted ventral prostate epithelial cells
(3). Although androgen regulation of connexins has not
been established for the prostate gland, testosterone has been shown to
increase Cx32 expression in spinal cord motorneurons
(16).
In addition to altered Cx32 levels, there was a significant increase in the number of epithelial cells expressing Cx43 in adult estrogenized ventral prostates, which correlates with the previously documented accumulation of basal cells in that tissue (10). In the normal adult prostate, epithelial cells expressing Cx43 are infrequent (24); thus, the presence of large numbers of Cx43-expressing epithelial cells in estrogenized adult prostates could reflect a "switch" toward dedifferentiation. Similar findings were observed in immortalized mouse hepatocytes, where the expression of Cx43 correlated with dedifferentiation of those cells (47). Thus, it is possible that the estrogen-induced differentiation defects, hyperplasia and dysplasia occurring with maturation and aging of the ventral prostate may be mediated in part via alterations in Cx32 and Cx43 resulting in aberrant cell-cell communication.
In contrast to the seemingly delayed effect of estrogen exposure on
epithelial connexin expression, there was an early alteration in
mesenchymal/stromal connexin expression at the time of estrogen
exposure. Thus there was increased expression of Cx43 in periurethral
mesenchymal cells as well as an extension of Cx43-positive cells beyond
the periurethral smooth muscle sleeve into the proximal regions of the
prostatic mesenchymal pad. We have previously reported that neonatal
estrogen treatment leads to immediate proliferation of prostatic
periductal fibroblasts, particularly within the proximal ductal regions
thus creating a physical barrier between smooth muscle and epithelial
cells, which constrains branching morphogenesis and blocks the
essential paracrine communications which normally control morphogenesis
(12). The increased GJIC via gap junctions composed of
Cx43 in periductal fibroblastic cells in estrogenized prostates may
reflect an increase in metabolic activity needed for their
proliferation. We have also shown that neonatal estrogenization results
in an immediate up-regulation of ER in periductal stromal cells
along the length of the developing prostatic ducts. Since evidence has
been presented that estrogens can directly regulate Cx43 expression
(28, 29), the present findings would indicate that Cx43
up-regulation in mesenchymal cells may be directly mediated via the
mesenchymal/stromal ER.
Neonatal estrogen exposure also resulted in an early decrease in prostatic epithelial E-cadherin staining intensity at day 6 when directly compared with control prostates, suggesting apposing effects of neonatal estrogen exposure on Cx43 and E-cadherin expression. By day 30, E-cadherin negative epithelial foci were observed, whereas in the aged estrogenized rats, E-cadherin was reduced across all epithelium in general and was absent in dysplastic epithelial cells. When colocalizing Cx32 and E-cadherin in aged estrogenized ventral prostates, reduced expression of both molecules was noted in normal appearing regions, whereas epithelial dysplasia was associated with a complete loss of Cx32 and very low E-cadherin staining. These data are in accordance with previously reported differentiation defects in estrogenized epithelium, particularly in the ventral lobe. Cell-cell adhesion and communication are intimately related; cells expressing connexins can assemble GJ only when cadherins are also expressed (14, 48, 49). E-cadherin was reported to function as a tumor suppressor protein, particularly as a suppressor of tumor cell invasion (36). E-cadherin expression is decreased in high grade prostate cancer and decreased E-cadherin expression is causally related to prostate cancer progression and invasiveness (33, 50, 51). As decreased expression of E-cadherin is associated with dedifferentiation, invasion and metastatic potential of tumor cells and perturbed GJIC is implicated in carcinogenesis, these dysplastic foci could represent the preinvasive state of transformed epithelial cells.
In conclusion, we found evidence that Cx43 is expressed in undifferentiated and mature basal cells as well as UGS mesenchymal cells, whereas Cx32 is expressed by differentiated prostate epithelial cells and E-cadherin expression increases with age and differentiation. Thus expression of Cx32 and E-cadherin may mark the differentiated state, and that of Cx43 the undifferentiated proliferating state in the prostate epithelium. Neonatal estrogenization of the prostate increases Cx43 and decreases Cx32 as well as E-cadherin expression, which may indicate a "switch" from differentiation to epithelial dedifferentiation. Estrogen-induced changes in the expression of E-cadherin and Cx32 and Cx43, and their assembly into GJs may result in defective cell-cell communication and impaired cell-cell adhesion, and may be one of the key mechanisms through which changes toward a dysplastic state are mediated.
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Footnotes |
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Received July 11, 2000.
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