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Short Communications |
From the Cytokine/Cytokine Receptor Laboratory,*
LINK Laboratories, University of Massachusetts Cancer Center,
University of Massachusetts Medical School, Worcester; and the
Department of Pathology,
and the Division of
Hematology/ Oncology,
University of
Massachusetts/Memorial Health Care, Worcester, Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(involved in ligand recognition), and gp130 (involved in signal
transduction) in cultured normal and malignant prostate-derived
epithelial cell lines. In the DU-145 prostate carcinoma cell
line, rhIL-11 stimulates a transient and dose-dependent
increase in the tyrosine 705-phosphorylated, active form of
STAT3 (STAT3 P-Tyr705), involved in the downstream signaling of
IL-11R and other members of the gp130-dependent receptors. The ability
of IL-11 to activate STAT3 in prostate-derived cells may be
mechanistically important, given recent data suggesting that
constitutively activated STAT3 may be associated with the malignant
phenotype. In 51 human primary tissues derived from normal
prostate, benign prostatic hyperplasia, and prostate
carcinomas, IL-11R and gp130 were commonly
expressed, with a statistically significant elevation in the
expression of IL-11R in prostate carcinoma. Also, the
tyrosine-phosphorylated, activated form of STAT3 was observed
more prominently in the nuclei of cells residing in malignant glands
compared to those in nonmalignant samples. Thus, the IL-11
receptor system is up-regulated in prostate carcinoma, and may
be one part of a cytokine network that maintains STAT3 in its activated
form in these tissues.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The IL-11 receptor (IL-11R) mediates the action of IL-11, a 19.1-kd
pleiotropic cytokine that was initially cloned from a bone-marrow
stromal cell line.2
Whereas the hematopoietic effects of
IL-11, which include stimulation of megakaryocyte maturation and
platelet production,3
and growth stimulation of
CD34+ hematopoietic progenitor
cells,4
have been well studied, this cytokine has also
been shown to mediate inhibition of adipogenesis,4
stimulation of osteoclasts,5
and cytoprotection of gut
mucosa.6-9
The IL-11 receptor is a member of a family of
cytokine receptors, sometimes referred to as the gp130-dependent family
of receptors, which includes the receptors for IL-6, leukemia
inhibitory factor, ciliary neurotrophic factor, oncostatin M, and
cardiotrophin.10
The subunit of the IL-11R, IL-11R,
is required for high affinity binding of the ligand; on ligand binding,
gp130, the subunit responsible for signal transduction, is recruited to
the receptor complex.11
It is not known whether
IL-11R-associated gp130 undergoes homodimerization, as it does in the
case of the IL-6 receptor, or if an additional, as yet unidentified,
subunit is involved.12
Among the signaling systems
activated by IL-11R and other members of this receptor family is the
JAK-STAT pathway. On ligand binding, these receptors activate members
of the JAK kinase family; these kinases phosphorylate tyrosine residues
in the cytoplasmic domains of the gp130 subunit, which in turn serve as
docking sites for members of a family of latent transcription factors,
the so-called signal transducers and activators of transcription
proteins, ie, STAT proteins.13,14
These recruited STAT
proteins undergo tyrosine phosphorylation, which permits their
dimerization and translocation to the nucleus where they alter gene
expression.15
Indeed, IL-11 has been shown to activate the
JAK1 and JAK2 receptor-associated kinases,16,17
triggering
the activation of STAT1 and STAT3.12,18
The latter action
may be especially important, as constitutive or aberrant activation of
STAT3 has recently been associated with the malignant phenotype.
Evidence for this includes: 1) constitutively activated STAT3 has been
reported in a variety of carcinomas and hematological
malignancies,19-24
2) cell transformation by
src seems to be associated with STAT3
activation,25,26
3) a mutant form of STAT3 that
spontaneously dimerizes and self-activates can act as an
oncogene,27
and 4) transfection of cell lines with
dominant-negative forms of STAT3 results in growth suppression and/or
induction of apoptosis.23,24,28
Other signaling systems
that may be activated by the IL-11R include MAP kinase, the ribosomal
S6 protein kinase, pp90rsk,29
src-family tyrosine kinases, eg, p60src and
p62yes, and phosphatidylinositol-3
kinase.30,31
Two developments prompted this study. First, there is evidence that one member of the cytokine family that activates the JAK-STAT pathway, IL-6, may be important in prostate biology. IL-6 is present in seminal fluid and elevated plasma levels of this cytokine have been associated with increased morbidity in prostate cancer patients.32 In addition, IL-6 acts as an autocrine growth factor in several prostate cancer cell lines, and this growth stimulation is accompanied by activation of STAT3.33 These data suggest that other members of this cytokine family might also be important in both normal and malignant prostate epithelial cells. Second, using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based screen for the expression of a number of prototypical cytokines and their receptors, we have discovered that one of the potential autocrine loops expressed by a normal human prostate epithelial cell line involves IL-11 and its receptor. As a result, we investigated the expression of components of the IL-11 system in prostate-derived cells and tissues.
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Materials and Methods |
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Normal human prostate epithelial cells were obtained from Clonetics (San Diego, CA); these cells were cultured for 2 to 4 passages in a defined medium as previously described.34 Culturing of the DU-145, PC-3, and LNCaP prostate carcinoma cell lines (all obtained from the ATCC, Rockville, MD) were performed as outlined previously.35 Recombinant human IL-11 (rhIL-11) was obtained from R&D Systems (Minneapolis, MN).
Detection of IL-11 and IL-11R mRNA by RT-PCR
The basic RT-PCR methodology used here has been
described.34
For the detection of IL-11 mRNA, the
following primers were used: sense: 5'-ACT GCT GCT GCT GAA GAC TCG GCT
GTG A-3', antisense: 5'-ATG GGG AAG AGC CAG GGC AGA AGT CTG T-3'; for
IL-11R, sense: 5'-GCC AAG CAG CCG ACT ATG AGA A-3', antisense:
5'-AGT AGC CGA GGG TGT GGT TGG A-3'. Amplification was performed in a
Stratagene Robocycler Gradient 40 thermal cycler (Stratagene, La Jolla,
CA) under the following conditions: denaturation, 94°C, 45 seconds;
annealing, 63°C for IL-11, 64°C for IL-11R, 45 seconds;
extension 72°C, 2 minutes; 35 cycles followed by a 10-minute
polishing step at 72°C. PCR products (expected sizes: 322 bp for
IL-11, 712 bp for IL-11R) were resolved by electrophoresis using
1.5% agarose gels containing ethidium bromide. To confirm the identity
of the PCR products, a Southern blotting technique was used. Gels were
denatured in 0.2 N NaOH, 0.6 mol/L NaCl for 30 minutes, then washed in
25 mmol/L sodium phosphate buffer, pH 6.5; DNA fragments were
transferred onto a GeneScreen nylon membrane (New England
Nuclear-Dupont, Boston, MA) in the latter buffer overnight. The
following antisense oligonucleotides to internal sequences within the
expected PCR products, IL-11, 5'-GAT CTG GCT TTG GAA GGA CGG TGG TGG
CT-3', and IL-11R, 5'-GGA CGG TAC TGC AAA CGG AAC TTG AGC A-3', were
32P-end-labeled with T4 polynucleotide kinase and
used to probe the membrane in a hybridization buffer consisting of 2x
standard saline citrate (SSC), 50% deionized formamide, 10% dextran
sulfate, 0.02% bovine serum albumin, 0.02% polyvinyl-pyrrolidone,
0.02% Ficoll, 1% sodium dodecyl sulfate (SDS), and 500 mg/ml tRNA
overnight at 42°C on an orbital shaker. The membrane was then washed
in 2x SSC, 1% SDS at 55°C (20 minutes), two washes (15 minutes) in
0.1x SSC, 0.1% SDS, 55°C, and one 5-minute wash in 0.1% SSC at
room temperature, then sealed and exposed to Kodak BioMax MS film
(Eastman-Kodak, Rochester, NY) for 2 hours.
Secretion of IL-11 by Cell Lines as Determined by Enzyme-Linked Immunosorbent Assay
Normal and malignant cell lines (see above) were plated in their respective growth media at 1 x 105 cells/well in six-well dishes and incubated in a humidified 37°C incubator in a 95% air-5% CO2 atmosphere for 96 hours. Culture media incubated without cells served as controls. Conditioned media was then harvested and stored at -70°C, and cells were trypsinized and counted using a hemocytometer. The conditioned media was thawed and centrifuged briefly before assay for soluble IL-11 protein using a commercially available enzyme-linked immunosorbent assay kit (R&D Systems).
Immunoblotting of STAT3 Phosphorylated at Tyr705
DU-145 prostate carcinoma cells (0.5 x 106) were plated in minimal essential medium containing 0.5% fetal bovine serum and incubated at 37oC for 48 hours to reduce basal levels of activated STAT3. Cells were then incubated in serum-free minimal essential medium for 4 hours, then treated with serum-free medium containing various concentrations of rhIL-11 for periods of up to 60 minutes. Cells were lysed in 62.5 mmol/L Tris-HCl, pH 6.8, 2% SDS, 10% glycerol, 50 mmol/L dithiothreitol, 0.1% bromphenol blue, heated to 95oC for 5 minutes, placed on ice, and loaded onto 10 to 15% gradient SDS-polyacrylamide gel electrophoresis gels (Amersham Pharmacia, Piscataway, NJ). After electrophoresis in a PhastSystem apparatus (Amersham Pharmacia), gels were electrotransferred onto nitrocellulose membranes; these membranes were analyzed for the presence of Tyr705-phosphorylated STAT3 using an antibody from New England Biolabs (Beverley, MA), according to the manufacturer’s procedures.
Immunohistochemical Analysis of Prostatic Tissues and Cell Lines
Formalin-fixed, paraffin sections (5 µm) of normal prostate,
benign prostatic hyperplasia, and prostate carcinoma were obtained
either from the Cooperative Human Tissue Network (Columbus, OH) or the
Department of Pathology at the University of Massachusetts/Memorial
Health Care System (Worcester, MA) under a human subjects protocol
approved by the University of Massachusetts Medical School human
subjects institutional review board. These sections were deparaffinized
by heating the slides to 60°C for 15 minutes and then subjecting them
to two 5-minute changes in 100% xylene; the sections were then
rehydrated by serial incubations in 100%, 90%, and 80% ethanol,
followed by phosphate-buffered saline (PBS). The sections were then
subjected to an antigen retrieval procedure: slides were placed in 10
mmol/L sodium citrate, pH 6.0, autoclaved at 121°C for 10 minutes,
then placed in PBS for 30 minutes. In the case of cell lines, cultured
cells were harvested by trypsinization and centrifuged onto
poly-L-lysine-treated glass slides, or the cells were
plated in their appropriate growth media on glass slides and grown for
24 hours; the cells were then fixed for 5 minutes in methanol at
-20°C. After this, specimens were treated with methanol containing
0.3% H2O2 for 5 minutes to
inactivate endogenous peroxidase activity. The samples were washed with
PBS and nonspecific binding sites blocked by incubating with 5% goat
serum in PBS for 90 minutes in a humidified chamber at room
temperature. Samples were then incubated for 60 minutes at room
temperature with rabbit anti-human IgG polyclonal antibodies to
IL-11R or gp130 (Santa Cruz Biotechnology, Santa Cruz, CA) or rabbit
polyclonal IgG controls (Santa Cruz Biotechnology) at concentrations of
3.5 µg/ml (IL-11R) or 1.0 µg/ml (gp130) in PBS containing 5%
goat serum. Specimens were then rinsed in wash buffer (PBS containing
0.5% bovine serum albumin, 0.1% Tween-20) and incubated for 30
minutes with biotinylated goat anti-rabbit IgG (rabbit ABC staining
kit, Santa Cruz Biotechnology) diluted according to the manufacturer’s
protocol. Next, a solution of avidin-conjugated horseradish peroxidase
(ABC staining kit) was applied for 30 minutes, according to the
manufacturer’s recommendations. Slides were then rinsed twice in wash
buffer and treated at room temperature with a
H2O2/3-amino-9-ethylcarbazole
substrate solution prepared as recommended by the manufacturer (Sigma
Chemical Co., St. Louis, MO): color development time was in the range
of 4 to 8 minutes. To confirm the specificity of the anti-IL-11R
staining, the anti-IL-11R antibody was preincubated for 2 hours at
room temperature with a fivefold excess by weight of the specific
IL-11R peptide that this antibody was raised against (Santa Cruz
Biotechnology) before using this antibody in the above-described
immunostaining method. This preabsorption procedure was found to block
immunostaining in prostate tissues, indicating that the staining
observed was specific for IL-11R. Similarly, preincubation of the
anti-gp130 antibody with a 10-fold excess of the specific gp130 peptide
that this antibody was raised against (Santa Cruz Biotechnology) also
blocked tissue staining. None of the tissues treated with control,
nonspecific antibodies demonstrated staining.
A subset of paraffin sections was also screened for the presence of STAT3 phosphorylated at Tyr705 (STAT3 P-Tyr705), the activated form of STAT3 that is generated downstream of IL-11R/gp130 activation. Sections were processed and stained using a 1:100 dilution of a rabbit polyclonal IgG anti-human STAT3 P-Tyr705 antibody (Cell Signaling Technology, Beverly, MA), or rabbit polyclonal IgG controls using the same immunohistochemical methodology described above, except that the incubation with the primary antibody was performed for 24 hours at 4°C and the secondary antibody incubation time was increased to 1 hour. No staining is observed if nonspecific rabbit polyclonal IgG is used. To further determine the specificity of the staining, the anti-STAT3 P-Tyr705 antibody was preabsorbed for 2 hours at room temperature with a 10-fold excess by weight of the phosphorylated peptide which the antibody was raised against (SAAPY*LKTK, where Y* is a phosphotyrosyl residue; a gift from Dr. Nicole Stark, Cell Signaling Technology). This absorption procedure completely eliminated the nuclear staining of the prostate tissue samples
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Results |
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As part of our laboratory’s effort to uncover novel autocrine and
paracrine axes that may play important functional roles in the
prostate, we examined a commercially obtained normal prostate
epithelial cell line (referred to as PrECs) for the expression of a
variety of cytokines, growth factors, and their cognate receptors using
an RT-PCR-based screen. Among the factors tested were interleukins 1
( and ß) through 15, and their receptors, excepting the receptors
for IL-12, 13, and 14. One of the salient findings of this study was
the co-expression of IL-11 and its receptor in the PrECs (Figure 1A
, lane 2). To determine whether
co-expression of IL-11 and IL-11R occurred in malignant prostate
epithelial cells as well, we also tested several frequently studied
prostate carcinoma cell lines, DU-145, PC-3, and LNCaP cells, for the
presence of these mRNAs using RT-PCR. As shown in Figure 1A
, each of
these cell lines also expressed both IL-11 and IL-11R. The
identities of these mRNAs were confirmed by Southern blotting using
internal probes specific to the respective sequences. We then
determined if these mRNAs were expressed as proteins in these cells.
Cell lines were plated in their respective growth media and incubated
for 96 hours; the conditioned media was then harvested and assayed for
human IL-11 using an enzyme-linked immunosorbent assay. Each of the
three cell lines tested (PC-3 cells were not studied) secreted
IL-11 (Figure 1B)
; DU-145 cells expressed this cytokine at the highest
level (97.4 ± 1.6 pg/105
cells), followed
by PrECs (57.4 ± 5.1 pg/105
cells), then
LNCaP cells (33.1 ± 13.2 pg/105
cells).
Control media, ie, media that was incubated in the absence of cells,
contained less than detectable levels of human IL-11 (<8 pg/ml). By
immunohistochemistry, the specific expression of IL-11R was
demonstrated in all four of these cell lines (for examples, see Figure 1C
). All these cell lines stained positively for gp130, the other IL-11
receptor subunit (data not shown). That this IL-11 receptor is
functional was demonstrated in studies with serum-starved DU-145 cells.
rhIL-11 was able to mediate a transient activation of the
phosphorylation of STAT3 on Tyr705 (STAT3 P-Tyr705) in these cells,
with a peak at 10 minutes and a return to basal levels by 60 minutes;
this activation was also dose-dependent (Figure 1D)
. Thus co-expression
of IL-11 and its receptor, ie, a potential autocrine loop, is commonly
observed in human cultured prostate cells.
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We then asked if components of the IL-11 system were present in
primary prostate tissues. Twenty-three primary prostate carcinomas
(with combined Gleason scores ranging from 6 to 9) and 28 nonmalignant
specimens (normal prostate or BPH) were analyzed for the expression of
IL-11R by immunohistochemistry. Several examples of these
immunostains are presented in Figure 2
.
It was noted that the epithelial cells of the nonmalignant specimens
displayed weak staining for IL-11R (Figure 2A)
, whereas more
frequent and prominent staining occurred within the high-grade
prostatic intraepithelial neoplasia (PIN) and invasive carcinoma
(Figure 2, B–D)
. Staining was observed in the stroma of all
prostate-derived specimens. To quantify these observations, epithelial
cells within the glands of the prostate samples were scored for
positive staining using the following scale: if no cells were positive,
a score of 0 was given; if >0 but 
25% of the cells stained
positively, a score of 1+ was given; if >25 but 50% of the cells
were positive, a score of 2+ was assigned; and if the number of
positive cells was >50%, a score of 3+ was given. Fourteen of the 23
carcinomas tested had a score of 3+ (61%) for IL-11R staining,
representing frequent expression of this receptor, whereas only nine
(39%) had scores of 2+ or 1+, representing moderate to low frequency
of IL-11R expression; none of the carcinoma samples stained
negatively (Table 1)
. In contrast, among
the 28 nonmalignant samples, six (21%) displayed no staining for
IL-11R, 22 (79%) had scores of 2+ or 1+, and none had a 3+ score.
Statistically, the scoring difference between the malignant
versus nonmalignant samples was highly significant
(P < 0.001) using a two-sided Fisher’s exact
test. There was no significant association, however, between IL-11R
staining and Gleason score, nor was there was any significant
difference in extent of IL-11R staining between BPH and normal
prostate tissues. These results indicate that IL-11R may become
up-regulated during the malignant transformation of prostate epithelial
cells, and/or that there is an expansion of an IL-11R-expressing
cell type that occurs during this process. We also performed
immunohistochemical staining for gp130, the signal transducing
component of the IL-11 receptor; gp130 was universally expressed in the
epithelial and stromal portions of these samples (data not shown), as
has been observed in many other tissues and cell types.10
We were unable to obtain an antibody to human IL-11 that was
satisfactory for the immunostaining of formalin-fixed paraffin
sections; as such, we were unable to determine whether potential IL-11
autocrine or paracrine axes are found in these prostate specimens.
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We then asked if the activated form of STAT3, ie, STAT3
phosphorylated at Tyr705 (STAT3 P-Tyr705), which would be produced as a
consequence of activation of the IL-11R, other members of the
gp130-dependent family of receptors, or certain growth factor receptors
such as erbB1,36
were present in these prostate-derived
tissues. An immunohistochemical assay was developed that used
antibodies that specifically recognize only this phosphotyrosine form
of STAT3. Because STAT3 P-Tyr705 is the species that dimerizes, enters
the nucleus, and acts as a transcription factor,15
it
would be predicted that one would observe primarily nuclear staining in
tissues where STAT3 is activated. A total of 21 prostate carcinomas and
28 specimens of normal or BPH were immunostained for STAT3 P-Tyr705. As
shown in Figure 3
, nuclear staining was
obtained in the glandular epithelial cells of both the malignant
(Figure 3A)
and nonmalignant samples (Figure 3B)
. The immunostains were
quantitated using the scoring system described above for IL-11R
staining. As in the case of IL-11R, it was noted that the epithelial
cells in many of the nonmalignant specimens stained relatively weakly
for STAT3 P-Tyr705 as compared to those in the malignant samples. For
example, 15 of the 21 carcinomas (71%) displayed frequent staining for
STAT3 P-Tyr705 (>50% of the cells staining positively), four (19%)
displayed low to moderate staining (1+ or 2+), and only two samples
were negative for this form of the protein (Table 2)
. In contrast, seven of the 28
normal/BPH samples (25%) did not stain for STAT3 P-Tyr705,19 (66%)
exhibited low to moderate staining (1+ or 2+), and only two displayed a
high percentage of positively staining cells (3+). The scores for the
malignant samples were significantly different from the nonmalignant
(P = < 0.0001) using a two-sided Fisher’s
exact test. A comparison of the scores for IL-11R expression and
STAT3 P-Tyr705 among the benign samples reveals that there is some
discordance between the two. In at least five cases, moderate
expression of activated STAT3 was observed in samples where IL-11R
was absent from the epithelial cells. This suggests that cytokines or
growth factors other than those that activate the IL-11 receptor, or
some other mechanism, are contributing to the activation of STAT3 in
these cases.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit is elevated in prostate carcinoma relative to their
BPH or normal prostate counterparts. Furthermore, the
tyrosine-phosphorylated, activated form of STAT3, a signal transducing
protein downstream of the IL-11 and other cytokine receptors, appears
to be more prominent in primary prostate carcinoma cells compared to
the epithelial cells of BPH or normal prostate. The presence of the
IL-11 system in prostate tissue is not without precedent. Douglas and
colleagues37
found the mRNA for IL-11R in 15 of 15
primary breast carcinomas; IL-11 has also been reported in some breast
cancer cell lines.38,39
A recent immunohistochemical-based
study from our laboratory revealed that the malignant epithelial cells
of 41 of 44 primary human ovarian tumors co-express IL-11R and
gp130, and that co-expression of IL-11 and its receptors are frequently
observed in cell lines derived from both a variety of solid tumors and
hematological malignancies.40
Thus the IL-11 system may be
more commonly expressed in malignant tissues and some of their normal
counterparts than originally appreciated. The exact function of IL-11 and other JAK-STAT activating cytokines in the prostate remains unclear. IL-6, which shares many overlapping actions with IL-11 in a number of cell systems, has been shown to activate androgen receptor-mediated gene expression in a STAT3-dependent manner in LNCaP prostate cancer cells.41 Importantly, IL-6 was found to mediate androgen receptor activation synergistically with androgens, but was capable of triggering androgen receptor activation in the absence of androgen.41 Thus in the normal prostate IL-6 (and IL-11) might act to sensitize androgen receptor-expressing prostate epithelial cells to the actions of androgens, whereas in the case of malignancy, up-regulation of these STAT3 activating cytokine systems might drive androgen receptor activation in the absence of androgens, thereby playing a role in the development of androgen independence. Another potentially relevant finding is that IL-11-expressing breast cancer cells can up-regulate the expression of aromatase in breast adipose stromal cells; by this paracrine interaction, the carcinoma cells might increase the level of stromal cell-generated estrogen.38 Based on these observations, the relationship between expression of JAK-STAT activating cytokines and sex steroid metabolism in steroid-response tissues such as prostate and breast deserves further study. One may also consider the potential role of the IL-11 system in aspects of the biological behavior of prostate carcinoma, such as the predilection of this malignancy to metastasize to bone. Because IL-11 is produced by bone-marrow stromal cells,3 IL-11R-bearing prostate carcinoma cells might be chemotactically attracted to this site; alternatively, if IL-11 serves as a growth or survival factor for these cells, the IL-11-rich bone marrow might be a hospitable environment for metastasizing cells.
The presence of the activated form of STAT3 and its up-regulation in prostate carcinoma, has important implications in terms of prostate cancer biology. As previously discussed, there is a growing body of evidence associating constitutive or aberrant activation of STAT3 with oncogenic transformation in human cancers.19-28 Constitutively activated STAT3 has recently been reported in prostate carcinoma cell lines;33 furthermore, transfection of these cells with dominant-negative forms of STAT3 triggers a suppression of their proliferation.42 The data presented here provides evidence that activated forms of STAT3 occur in primary prostate carcinomas as well. Based on the findings presented here that the IL-11 receptor is commonly and prominently expressed in prostate cancers, that IL-11 can trigger STAT3 activation in prostate-derived cells, and the recent data that IL-6 may be an important inducer of STAT3 activation and prostate epithelial cell growth,33,42 one may postulate that there are multiple cytokine networks involving the gp130-dependent receptors and other systems operating in prostate carcinoma whose function is to maintain STAT3 in an activated state, thus helping to drive the malignant phenotype.
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Footnotes |
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Supported by an American Cancer Society institutional grant, the University of Massachusetts Cancer Center, and the Department of Pathology, University of Massachusetts/Memorial Heath Care.
Accepted for publication September 25, 2000.
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 C. P. Castro, D. Giacomini, A. C. Nagashima, C. Onofri, M. Graciarena, K. Kobayashi, M. Paez-Pereda, U. Renner, G. K. Stalla, and E. Arzt Reduced Expression of the Cytokine Transducer gp130 Inhibits Hormone Secretion, Cell Growth, and Tumor Development of Pituitary Lactosomatotrophic GH3 Cells Endocrinology, February 1, 2003; 144(2): 693 - 700. [Abstract] [Full Text] [PDF]
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 M. Dolled-Filhart, R. L. Camp, D. P. Kowalski, B. L. Smith, and D. L. Rimm Tissue Microarray Analysis of Signal Transducers and Activators of Transcription 3 (Stat3) and Phospho-Stat3 (Tyr705) in Node-negative Breast Cancer Shows Nuclear Localization Is Associated with a Better Prognosis Clin. Cancer Res., February 1, 2003; 9(2): 594 - 600. [Abstract] [Full Text] [PDF]
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H. Steiner, S. Godoy-Tundidor, H. Rogatsch, A. P. Berger, D. Fuchs, B. Comuzzi, G. Bartsch, A. Hobisch, and Z. Culig Accelerated in Vivo Growth of Prostate Tumors that Up-Regulate Interleukin-6 Is Associated with Reduced Retinoblastoma Protein Expression and Activation of the Mitogen-Activated Protein Kinase Pathway Am. J. Pathol., February 1, 2003; 162(2): 655 - 663. [Abstract] [Full Text] [PDF]
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L. B. Mora, R. Buettner, J. Seigne, J. Diaz, N. Ahmad, R. Garcia, T. Bowman, R. Falcone, R. Fairclough, A. Cantor, et al. Constitutive Activation of Stat3 in Human Prostate Tumors and Cell Lines: Direct Inhibition of Stat3 Signaling Induces Apoptosis of Prostate Cancer Cells Cancer Res., November 15, 2002; 62(22): 6659 - 6666. [Abstract] [Full Text] [PDF]
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M. Masuda, M. Suzui, R. Yasumatu, T. Nakashima, Y. Kuratomi, K. Azuma, K. Tomita, S. Komiyama, and I. B. Weinstein Constitutive Activation of Signal Transducers and Activators of Transcription 3 Correlates with Cyclin D1 Overexpression and May Provide a Novel Prognostic Marker in Head and Neck Squamous Cell Carcinoma Cancer Res., June 1, 2002; 62(12): 3351 - 3355. [Abstract] [Full Text] [PDF]
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D. Giri, M. Ozen, and M. Ittmann Interleukin-6 Is an Autocrine Growth Factor in Human Prostate Cancer Am. J. Pathol., December 1, 2001; 159(6): 2159 - 2165. [Abstract] [Full Text] [PDF]
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