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From the Departments of * Department of Surgery,
Division of Urology and Laboratory Medicine
and Pathology, UMDNJ-New Jersey Medical School, Newark, New Jersey, and VA
Medical Center, East Orange, New Jersey.
| Correspondence to: Dr Hosea F. S. Huang, Department of Surgery, Division of Urology, UMD-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103 (e-mail: huanghf{at}umdnj.edu). |
| Received for publication March 13, 2002; accepted for publication May 23, 2002. |
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Abstract |
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, -ß, and -
in human prostate tissues
exhibiting different pathologic conditions. In histologically normal
epithelium, both RAR- and - were present throughout the
epithelium with minimal nuclear accumulation. RAR-ß was present only in
basal epithelial nuclei. On the contrary, RAR- was significantly
increased in the nuclei of luminal epithelial cells, and both RAR-ß and
- were increased in basal and luminal epithelial nuclei in glands
exhibiting benign prostatic hyperplasia (BPH). RAR- was also increased
in luminal epithelial nuclei in glands exhibiting prostatic intra-epithelial
neoplasia (PIN). In these glands, RAR-ß was persisting in basal
epithelial nuclei that were also RAR- positive. In low- and
intermediate-grade cancerous glands, RAR- was also significantly
increased in luminal epithelial nuclei, and a strong RAR- signal was
seen in some cells. RAR-ß was absent in these glands. Both RAR-
and - were also increased in high-grade cancer cells. In conclusion,
current results demonstrated changes in cellular distribution of RAR-
and - in human prostate tissues exhibiting different pathologies. These
results suggest links between altered RAR signaling and deregulated cell
growth and/or tumorigenic transformation of prostate epithelial cells.
Key words: Prostate carcinoma
Retinoids exert their cellular effects by binding to and activation of
retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are
members of the steroid and thyroid hormone receptor superfamily
(Evans, 1988;
Chambon, 1995). These receptors
are transcription factors that, upon ligand binding, modulate the expression
of target genes and result in cascades of biochemical events leading to
changes in cellular function (Mangelsdorf
et al, 1995). Aberrant expression and signaling of RARs and RXRs
have been linked to various malignancies, including those of the breast, lung,
cervix, and promyeloytic leukemia (de The
et al, 1990; Gebert et al,
1991; Roman et al,
1993; Geisen et al,
1997). While the importance of RAR signaling in prostate cell
biology and pathophysiology has also been suggested
(Huang et al, 1997;
Richter et al, 1999), and
abnormal retinoid nutritional states in human prostate cancer tissues have
been reported (Pasquali et al,
1995), the function of RAR signaling in the pathogenesis and/or
progression of prostate neoplasia remained undefined. By using in situ
hybridization, Lotan et al
(2000) reported the presence
of messenger RNA (mRNA) transcripts for RAR- and - in human
prostate epithelium but observed no changes in these transcripts under
different pathophysiologic conditions. On the other hand, Gyftopoulos et al
(2000a,b)
reported increased RAR- in prostate cancer tissues and a correlation
between the abundance of RAR- and the grades of the disease, thus
suggesting a role of RAR- signaling in the progression of prostate
cancer. An overexpression of RAR- has also been reported in tumorigenic
rat prostate epithelial cells (Richter et
al, 1999). In order to understand the function of RAR signaling in
human prostate cancer biology, the present study examined the cellular
distribution of RAR-, -ß, and - in normal and pathologic
human prostate tissues. Results of these experiments demonstrated differences
in the cellular distribution of these receptors in tissues exhibiting
different pathophysiology. These results emphasize the importance of RAR
signaling in prostate cell biology and perhaps the genesis and progression of
prostate cancer.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Specificity of RAR Antibodies
The antibodies used in the present experiment were affinity-purified rabbit
polyclonal antibodies raised against peptides mapping at the carboxy terminal
of RAR-, -ß, and - of human origin (Santa Cruz
Biotechnology Inc, Santa Cruz, Calif). To verify the specificity of these
antibodies, recombinant human RAR-, -ß, and - proteins
(Wolfgang et al, 1997) were
immunoblotted using standard 10% sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (BioRad Laboratories, Hercules, Calif).
Immunostaining of RAR-, -ß, and -
The sections were deparaffinized in xylene and hydrated in graded ethanol,
and antigens (RARs) were retrieved by boiling the sections in 0.01 M Na
citrate (pH 6.0) for 30 minutes. Immunostaining of RAR-, -ß, and
- was performed using the DAKO Catalyzed Signal Amplification System by
procedures outlined by the manufacturer (DAKO Corp, Carpinteria, Calif). For
negative control, the primary antibodies were replaced with antibodies that
were incubated with 50-fold excess of corresponding purified peptide or
recombinant protein at 4°C overnight. For each specimen, immunostaining of
each RAR was performed at least twice at different times. In each section, 4
to 6 areas of similar pathological conditions were examined independently by 2
individuals (F.R. and H.F.S.H.) to establish the staining pattern for each
RAR. The intensity of staining in the nuclei or cytoplasm was scored 0 to 3
arbitrarily to reflect negative, light, moderate, and strong, respectively.
The pathological conditions were then diagnosed by 2 pathologists (A.J. and
F.F.) using HE-stained adjacent sections.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The Table summarizes the patterns of cellular distribution of RARs in human
prostate under different pathophysiologic conditions. In histologically normal
tissues (Figure 2A),
RAR- was uniformly distributed in glandular epithelium
(Figure 2B). Of the 61 glands
examined, low-moderate intensity of RAR- was detected in approximately
75% of luminal epithelial cells, and RAR- containing granules/vesicles
were frequently seen at the luminal edge of the epithelium. Immunostaining
intensity of RAR- in the nuclei was not significantly greater than that
in the cytoplasm (Figure 2B).
In contrast, RAR-ß was seen only in basal epithelial nuclei in more than
80% of normal glands (Figure
2C). Like RAR-, a low level of RAR- was also present
in normal epithelium without significant nuclear accumulation
(Figure 2D). Frequently,
RAR- was detected in basal epithelial nuclei of some glandular tissues
(Figure 2D).
|
Cellular distributions of RARs were altered in glands and cells exhibiting
different pathologies. In glands exhibiting BPH, RAR- was also present
throughout the epithelium but with increased intensity of RAR- in the
nuclei of luminal epithelial cells (Figure
2F). Unlike those in normal glands, moderate intensities of both
RAR-ß and - were present in epithelial cytoplasm, as well as in
basal and luminal epithelial nuclei in BPH glands
(Figure 2G and H).
In glandular epithelium containing prostatic intraepithelial neoplasia
(PIN), there was a significant increase in nuclear RAR- in luminal
epithelial cells. It was estimated that more than 80% of luminal epithelial
nuclei of the PIN exhibited a moderate to strong RAR- signal
(Figure 3B). In these glands,
RAR-ß was also present in basal epithelial nuclei
(Figure 3C) and in nuclei of
some basally located cells adjacent to cancerous glands or cells (Figures
3G and
4C). Unlike that in BPH glands,
RAR- was increased only in basal epithelial nuclei of glands exhibiting
PIN. Such increases were seen in 12 of the 15 specimens examined
(Figure 3D).
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In the low- and intermediate-grade cancerous glands, there was a general
increase in the RAR- signal in epithelial cells with 2 distribution
patterns that sometimes coexisted within the same specimen. In approximately
90% of the low-grade cancerous glands (Gleason grade 2), a moderate strength
signal of RAR- was present in most nuclei similar to that in the PINs
(data not shown). While a moderate to strong signal of RAR- was also
seen in the nuclei of intermediate-grade (Gleason grade 3) cancer cells
(Figure 3F), the number of such
nuclei appeared to be less than that of the lower grade cancer cells. In
approximately 60% of low- and intermediate-grade cancerous glands, a moderate
to strong RAR- signal was present in the cytoplasm of some cells with
or without significant nuclear staining (data not shown). In these glands,
RAR-ß was usually absent (Figure
3G), and RAR- was present in isolated cells with or without
nuclear staining (Figure
3H).
There was an even greater increase in RAR- in highgrade (Gleason
grade 4) cancer cells (Figure
4A). It was estimated that more than 80% of high-grade cancer
cells (8 specimens, n = 36 areas) contained high levels of RAR- in both
the nuclei and cytoplasm (Figure
4B). In 7 of 8 specimens, a moderate to strong intensity of
RAR- was present in the nuclei of high-grade cancer cells
(Figure 4D). The presence of
RAR-ß in high-grade cancer cells was negligible
(Figure 4C). Preadsorption of
antibodies with their respective antigen or recombinant protein eliminated the
immunostaining of each RAR (Figure 4E
through G).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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and - among tissues with
distinct pathologies and postulated that RAR- and - perhaps had
no significant role in prostate malignancy. On the other hand, Gyftopoulos et
al
(2000a,b)
reported an increased RAR- protein level that correlated with the
grades of prostate cancer, thus suggesting a link between altered RAR-
signaling and progression of the disease. Results of the current experiment
were consistent with the latter and further demonstrated increases of
RAR- in cells that were associated with BPH and PIN. In addition, we
observed differences in the expression and cellular distribution of RAR-ß
and - in human prostate cells that were associated with different
pathophysiologic conditions.
The presence of RAR- in normal epithelium with relatively weak
nuclear localization suggests that perhaps a minimal RAR- signaling is
sufficient for normal epithelial functions. The frequent appearance of
granular RAR- at the luminal edge of the epithelium might be due to the
crowding of the epithelium and has been reported previously
(Gyftopoulos et al, 2000b). On
the contrary, increases in nuclear RAR- in epithelial cells that were
associated with BPH, PIN and various grades of cancer imply that RAR-
signaling events might have been exaggerated in these cells. Of note,
increases in nuclear RAR- in BPH glands occurred while cytoplasmic
RAR- persisted, whereas that in the PIN, and the low- and
intermediate-grade prostate cancer glands occurred without the significant
presence of cytoplasmic RAR-. Such differences suggest variations in
the intracellular shuttling of RAR- protein. These effects were
dictated by disease states of the cell and could be attributed to the
induction or posttranslation modification of RAR-. Energy metabolism
and ligand availability have been shown to affect nucleotranslocation of the
progesterone receptor (Guiochon-Mantel et
al, 1991), and increased nuclear localization of RAR- has
been observed in rat prostate epithelial cells after castration (Huang et al,
unpublished data). The biphasic changes in RAR- intensities among low-,
intermediate-, and high-grade cancer cells were consistent with the findings
of Gyftopoulos et al (2000a).
These findings, together with an overexpression of RAR- mRNA in
tumorigenic rat prostate epithelial cells
(Richter et al, 1999),
emphasize the involvement of RAR- signaling in tumorigenic
transformation and/or deregulated cell growth of prostate epithelial cells. A
correlation between the expression of the Ki-67 antigen and RAR- in
prostate cancer cells (Gyftopoulos et al,
2000a) is consistent with a role for RAR- in deregulated
cell growth.
The presence of RAR-ß in basal epithelial cells of normal tissues was
consistent with its mRNA distribution
(Lotan et al, 2000). Because
of the absence of RAR-ß mRNA in malignant prostate glands and its
decrease in basal epithelial cells of adjacent normal glands, Lotan et al
(2000) postulated that
tumorigenic transformation of prostate cells was associated with a decrease in
RAR-ß expression. This postulate was based on the reported efficacy of
RAR-ß in growth suppression of lung cancer cells
(Houle et al, 1993) and
correlates between clinical outcome and increased RAR-ß in premalignant
oral lesions after isotretinoin administration
(Lotan et al, 1995). Results
of the current study, however, demonstrated the persistence of RAR-ß in
basal epithelial nuclei in epithelium exhibiting BPH and PIN. The cause for
such a discrepancy perhaps can be attributed to feedback regulation of
transcription and translation of the RAR-ß gene. In the rat prostate,
postcastration increases in RAR- mRNA were preceded by a decrease in
RAR- protein (Huang et al, unpublished data). Of note, RAR-ß
protein was also increased in epithelial cytoplasm and nuclei of luminal
epithelial cells in BPH glands. Such a phenomenon was not seen in normal
glands or in those exhibiting PIN. This finding thus suggests a distinct
relationship between RAR-ß signaling and BPH. The lack of RAR-ß in
low-grade cancer glands is consistent with the absence of basal epithelial
cells in such glands. In addition, RAR-ß was also detected in some
basally located cells in epithelium containing PIN neighboring cancerous cells
or glands. While the identity of these cells remains to be determined,
increased nuclear RAR-ß in these cells might reflect their response to
the presence of tumorigenic cells in their surroundings.
An increase in RAR- in basal epithelial nuclei of high PIN and BPH
glands suggests that basal epithelial cells of these glands might share
certain similarities and could contribute to the genesis of these pathologic
conditions. This postulate is based on a recent finding demonstrating that
estrogen-induced metaplastic transformation of mouse prostate cells involved
the proliferation of cells with basal cell phenotype
(Risbridger et al, 2001).
Alternatively, such an increase might reflect the response of basal epithelial
cells to abnormal or deregulated cell growth in the luminal compartment. Of
note, RAR- was also increased in luminal epithelial nuclei of BPH
glands but not of the PINs and most low-grade cancer cells. Such a difference
again distinguishes cells that associated with benign deregulated cell growth
and those with tumorigenic potential. Significant increases of RAR- in
some low-grade cancerous cells suggest that they might be undergoing further
tumorigenic changes, since a strong RAR- signal was also detected in
the nuclei of high-grade cancer cells.
RARs, as dimeric partners with RXRs, interact with the retinoic acid-responsive element on the promoter of target genes to modulate the expression of these genes causing changes in cellular activities (Mangelsdorf et al, 1995). The retinoid—RAR complex could also affect cellular function by interfering with gene expression via the c-jun/c-fos (AP-1) signaling pathway (Schule et al, 1991; Pfahl, 1993; Saatcioglu et al, 1994) that has been linked to oncogenesis (Angel and Karin, 1991). The AP-1 signaling pathway has been reported to mediate the cell growth effect of retinoid on human lung cancer cells (Wan et al, 1997), as well as the cell suppression effect of retinoid on ovarian cancer cells (Soprano et al, 1996) and Calu-6 human lung cancer cells (Fanjul et al, 1994; Chen et al, 1995).
Retinoic acid has been shown to stimulate cell growth in human prostate
tumor lines, including PC-3, LNCaP, and DU-145
(Fong et al, 1993; Esquenet et al, 1996;
Jones et al, 1997), but to
inhibit cell growth in primary human prostate cell lines
(Peehl et al, 1993), canine
prostate adenocarcinoma, and normal canine prostate epithelium
(Jones et al, 1997). These
results suggest that the tumorigenic transformation of prostate cells may
alter their growth response to retinoic acid. Dose-dependent and opposite
effects of testosterone on the expression of RAR- and - mRNAs in
nontumorigenic and tumorigenic rat prostate epithelial cells
(Richter et al, 1999) further
suggest that RAR signaling may mediate some of the effects of testosterone on
prostate cells; such effects may be altered after tumorigenic transformation.
The reported modulation of the growth of LNCaP cells by RXR analogs
(De Vos et al, 1997) and DU145
cells by the RAR- agonist and antagonist
(Fanjul et al, 1996; Lu et al, 1999) is also
consistent with the involvement of RAR and RXR signaling in prostate cancer
cell growth. In addition, interaction between RAR and other members of the
receptor family such as the vitamin D receptor
(Blutt et al, 1997;
Campbell et al, 1998) could
also affect the growth response of prostate carcinoma cells to retinoids. A
reduced retinoid concentration in cancerous tissue
(Pasquali et al, 1995) could,
on the one hand, trigger metaplasia and/or tumorigenic transformation of the
neighboring epithelial cells and result in new foci of cancer cells. On the
other hand, it could initiate feedback mechanisms and result in compensatory
increases of RAR proteins and alter the balance of different RAR signaling
events and downstream cellular effects. A combination of these changes could
thus contribute to the progression of the disease.
In summary, current results demonstrate distinct cellular distributions of
RAR-, -ß, and - in human prostate tissues that exhibit BPH,
PIN, and low- or high-grade cancer. These results implicate the RAR signaling
events in neoplasia of human prostate epithelial cells. The distinct
distribution pattern of these receptors under different pathologic conditions
may qualify them as adjuvant markers for specific disease states. Since
retinoids exert their cellular effects through RAR signaling, increased
nuclear RARs in prostate cancer cells may render these cells more vulnerable
to RAR analogs. In this regard, specific RAR- and - analogs have
been found to be effective in the suppression of prostate carcinoma cells
(Lu et al, 1999;
Hammond et al, 2001).
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Acknowledgments |
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, -ß, and - proteins used in the immunoblots. |
Footnotes |
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