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From the Department of Pathology, Baylor College of Medicine, Houston; and the Houston Department of Veterans Affairs Medical Center, Houston, Texas
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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18-fold in clinically localized prostate cancers when compared to
normal prostate tissue. Normal and neoplastic prostatic epithelial
cells in culture, with the exception of LNCaP cells,
secrete IL-6. Addition of exogenous IL-6 to primary epithelial cells in
culture or the LNCaP prostate cancer cell line leads to phosphorylation
of Stat-3 and increases in net cell proliferation. The concentration of
IL-6 receptor is increased eightfold in the prostate cancer tissues and
is increased in the cancer cells by immunohistochemistry. The increased
expression of IL-6 receptor is correlated with increased proliferation
of prostate cancer cells in vivo as assessed by Ki67
immunohistochemistry. These findings strongly support the hypothesis
that IL-6 acts as a significant autocrine growth factor in
vivo for primary, androgen-dependent prostate
cancers.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Prostate cancer is the most common cancer in American men and the second leading cause of cancer deaths in this group. There is evidence that IL-6 may play an important role as an autocrine growth factor in metastatic prostate cancer. It has been demonstrated by several laboratories that all of the commonly used prostate cancer cell lines (PC3, DU145, and LNCaP) express high-affinity receptors for IL-6.5-8 In addition, it has been shown that the PC3 and DU145 cell lines secrete IL-6,6-8 leading to a potential autocrine growth loop, and that neutralizing antibody to IL-6 decreases growth of these two cell lines.7 LNCaP does not secrete IL-66-8 and the effect of exogenous IL-6 on this cell line is controversial, with some groups showing growth stimulation7,9,10 and other groups showing growth inhibition.6,11,12 Thus, there is evidence that IL-6 can act as an autocrine growth factor for prostate cancer cell lines in vitro. However, all of these cell lines were established from metastatic prostate cancers and both PC-3 and DU145 are androgen-independent, so the extent to which IL-6 acts as a growth factor for primary human prostate cancers in vivo is not clear. Hobisch and colleagues13 have shown by immunohistochemistry that both IL-6 and IL-6 receptors are expressed at increased levels in clinically localized prostate carcinomas. However, the actual magnitude of the increased expression of IL-6 and IL-6 receptor in the tissues cannot be assessed quantitatively by immunohistochemistry and the biological consequences of this potential autocrine loop have not been established in vivo.
We have found that IL-6
protein concentrations are increased 18-fold in clinically localized
prostate cancers when compared to normal prostate tissue and that IL-6
is secreted by normal and neoplastic prostatic epithelial cells. IL-6
can act as a growth factor for both normal prostatic epithelial cells
and the LNCaP prostate cancer cell line. In addition, the concentration
of IL-6 receptor is increased eightfold in the prostate cancer tissues.
Most importantly, increased expression of IL-6 receptor is correlated
with increased proliferation in vivo as assessed by Ki67
immunohistochemistry. These findings demonstrate for the first that
there is a quantitatively significant increase in IL-6 and its receptor
in prostate cancer in vivo and that this increase is
strongly correlated with a biological significant parameter, ie,
proliferation. Thus IL-6 seems to be an important autocrine growth
factor for androgen-dependent human prostate cancer in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Samples of the benign peripheral and transition zone of the prostate or prostate carcinoma were taken from radical prostatectomies performed for treatment of clinically localized prostate cancer. Tissues were received fresh and portions snap-frozen in liquid nitrogen or, if from benign peripheral zone areas, used to establish primary cell cultures (see below). The frozen tissues were then analyzed by frozen section to confirm the presence or absence of carcinoma. The carcinoma tissues were 30 to 80% carcinoma by frozen section analysis.
Cell Culture, Production of Conditioned Medium, and Cell Growth Assays
Primary prostatic epithelial cultures were established using prostatic tissue samples from areas in the peripheral zone of radical prostatectomy specimens that were free from carcinoma as described previously.14 To prepare conditioned medium, primary epithelial cells were plated in 10-cm tissue culture dishes. When the cells were subconfluent epithelial growth medium was replaced with 8 ml of MCDB 153 medium containing insulin, transferrin, selenium, bovine serum albumin, and oleic acid (1% ITS+2; Sigma Chemical Co., St. Louis, MO). Conditioned medium was collected after 72 hours. The epithelial cells tolerated this treatment well and appeared healthy after this period.
PNT2, an immortalized but nontumorigenic prostate epithelial cell line, and LNCaP, DU145, and PC3 prostate cancer cells were maintained in RPMI 1640 containing 10% fetal bovine serum. Conditioned medium was collected by incubating subconfluent cultures of each cell line in 8 ml of RPMI 1640 containing 1% ITS for 72 hours.
For growth assays, primary epithelial cultures were plated at 1 x 105 cells per 35-mm dish and the next day refed with MCDB 153 with 1% ITS. Control plates were incubated in this medium and experimental plates were treated with 1 or 10 ng/ml of recombinant IL-6 (R&D Systems, Minneapolis, MN). Cells were harvested by trypsinization after 1 to 3 days and cell number determined by counting using a Coulter counter. LNCaP cells were plated at 5 x 104 cells per 35-mm dish and the next day refed with RPMI 1640 with 1% ITS. Control plates were incubated in this medium and experimental plates were treated with 10 or 100 ng/ml of recombinant IL-6. Cells were harvested by trypsinization after 1 to 3 days and cell number determined by counting using a Coulter counter.
Cell Cycle Analysis
LNCaP cells (2 x 105) were plated in 100-mm dishes and, after overnight incubation, medium was changed to RPMI 1640 containing 1% ITS with or without 100 ng/ml of IL-6 and incubated for 24, 48, and 72 hours. Both floating and attached cells were harvested and stained with propidium iodide for DNA cell-cycle analysis following a standard protocol. DNA content was measured using a flow cytometer (Epics XL-MCI; Beckman Coulter, Miami, FL) and cell cycle analysis was performed using Multi Cycle for Windows version 3.0 software (Phoenix Flow Systems, San Diego, CA).
Analysis of Stat-3 and Phosphorylated Stat-3
Prostatic primary epithelial cells or LNCaP cells (1 x 106 cells/10-cm plate) were treated with 10 ng/ml of recombinant IL-6 at 37°C. After treatment, the cells were washed with cold phosphate-buffered saline (PBS) and suspended in 0.2 ml of lysis buffer (10 mmol/L HEPES, pH 7.9, 10 mmol/L KCl, 0.1 mmol/L ethylenediaminetetraacetic acid, 0.1 mmol/L EGTA, 1 mmol/L dithiothreitol, 0.5 mmol/L phenylmethyl sulfonyl fluoride, 2 µg/ml leupeptin, 2 µg/ml aprotinin, and 0.5 mg/ml benzamidine). The cells were allowed to swell on ice for 15 minutes after which 6 µl of 10% Nonidet P-40 was added. The tube was then vigorously vortexed for 20 seconds and the homogenate centrifuged for 1 minute in an Eppendorf microcentrifuge at 4°C. The supernatant (cytoplasmic extract) was removed and stored at -80°C. The nuclear pellet was resuspended in 30 µl of ice-cold nuclear extraction buffer (20 mmol/L HEPES, pH 7.9, 0.4 mol/L NaCl, 1 mmol/L ethylenediaminetetraacetic acid, 1 mmol/L EGTA, 1 mmol/L dithiothreitol, 1 mmol/L phenylmethyl sulfonyl fluoride, 2 µg/ml leupeptin, 2 µg/ml aprotinin, and 0.5 mg/ml benzamidine) and the tubes incubated on ice for 30 minutes with intermittent vortexing. The tubes were then centrifuged for 5 minutes in an Eppendorf microcentrifuge at 4°C and the supernatant (nuclear extract) stored at -80°C. Western blotting was performed as described previously15 using 30 µg of extract protein per lane. Blots were incubated with either 0.1 µg/ml of anti-phospho-Stat3 (Y704) mouse monoclonal antibody (Upstate Biotechnology, Lake Placid, NY) or 0.2 µg/ml rabbit polyclonal anti-Stat-3 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) at 4°C for 12 hours and then incubated with the appropriate secondary antibody and antigen-antibody complexes visualized by enhanced chemiluminescence (Amersham, Arlington Heights, IL).
Immunohistochemistry (IHC)
Frozen tissue sections were fixed in acetone for 10 minutes and stored at -80°C. All sections were treated with Autoblocker (R&D Systems) to inhibit endogenous peroxidase and avidin/biotin (Vector Laboratories, Burlingame, CA) to block endogenous biotin. The sections were incubated with 0.5 µg/ml of anti-phospho-Stat3 (Y704) mouse monoclonal antibody (Upstate Biotechnology) or 10 µg/ml of anti-IL-6 receptor mouse monoclonal antibody (Sigma) at 4°C for 12 hours. After liberal washing with PBS, pH 7.4, sections were then incubated with biotinylated horse anti-mouse antibody at 7.5 µg/ml for 45 minutes at room temperature (Vector Laboratories). Sections were then washed with PBS containing 0.1% Tween 20 and incubated with avidin-biotin complex (Vectastain Elite, Vector Laboratories) for 15 minutes. The antigen-antibody reaction was demonstrated using diaminobenzidine as substrate and the sections then counterstained with hematoxylin. Ki67 immunohistochemistry was performed and staining quantitated as described previously.16
Enzyme-Linked Immunosorbent Assay (ELISA)
Cell extracts were prepared from snap-frozen tissues as described previously.15 Determination of the IL-6 and IL-6R concentration in the media and tissue extracts was performed by ELISA based on a quantitative sandwich immunoassay technique using kits from R&D Systems as described by the manufacturer. An aliquot of 100 µl of conditioned medium or 25 µl of tissue extract made to 100 µl with diluent (0.1% bovine serum albumin, 0.05% Tween 20, 10 mmol/L Tris, and 150 mmol/L sodium chloride, pH 7.3) was added per well. The IL-6 ELISA was linear between 3 to 300 pg/ml whereas the IL-6 receptor ELISA was linear between 2 to 200 pg/ml.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether IL-6 may act as an autocrine growth factor in
clinically localized prostate cancer the concentration of IL-6 was
determined in tissue extracts of 40 prostate cancers and 10 normal,
noncancerous tissue samples from radical prostatectomy specimens. In
all cases the presence or absence of cancer was assessed by frozen
section analysis before preparation of extracts and all cancer tissues
contained at least 30% cancer based by frozen section. Figure 1
shows the IL-6 content of prostate
cancers and benign prostatic tissue as determined by ELISA.
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Expression of IL-6 by Normal and Neoplastic Prostatic Epithelial Cells
To determine whether normal prostatic epithelial cells can produce IL-6, conditioned medium was collected from six different primary cultures of prostatic epithelial cells and from an immortalized but nontransformed prostatic epithelial cell line (PNT2) after 72 hours incubation and the cells counted. The concentration of IL-6 in the conditioned medium was then determined by ELISA. The primary cells secreted 609 ±90 (SD) pg of IL-6/24 hours/106 cells. The PNT2 cells secreted lower but still significant quantities of IL-6 (53 pg/24 hours/106 cells). In agreement with reports of other laboratories,6-9 LNCaP cells did not secrete detectable IL-6 into the media, whereas both PC3 and DU145 secreted quantities similar to the primary epithelial cells.
Phosphorylation of Stat-3 in Response to IL-6 in Prostatic Epithelial Cells
To determine whether functional IL-6 receptors are present on
LNCaP cells, these cells were treated with recombinant IL-6 cells,
fractionated into cytoplasmic and nuclear fractions, and total Stat-3
and phosphorylated Stat-3 assessed by Western blotting in each
fraction. As can be seen in Figure 2
,
Stat-3 protein is primarily cytoplasmic in untreated LNCaP cells and no
phospho-Stat3 protein is present, consistent with the lack of IL-6
secretion by these cells. After treatment with recombinant IL-6 there
is loss of cytoplasmic Stat-3 protein accompanied by an increase in
nuclear Stat-3 protein and nuclear phospho-Stat-3 protein. Thus LNCaP
cells express functional IL-6 receptor complexes that can phosphorylate
Stat-3 protein. Similar experiments with primary epithelial cells show
that IL-6 induces both translocation of Stat-3 into the nucleus and
increased phosphorylation of Stat-3 protein (data not shown).
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To determine the biological effect of IL-6 receptor complex
activation on prostatic epithelial cells, we determined the effect of
exogenous recombinant IL-6 on cell proliferation of both primary
prostatic epithelial cells and the LNCaP prostate cancer cell line.
Exogenous IL-6 at either 1 or 10 ng/ml lead to a statistically
significant increase in net cell proliferation in primary prostatic
epithelial cells after 3 days of treatment when compared to untreated
control cells (Figure 3A)
. Similarly,
IL-6 at 10 or 100 ng/ml lead to a statistically significant increase in
net proliferation of LNCaP cells after only 24 hours of treatment
(Figure 3B)
. The range of IL-6 concentrations used (1 to 100 ng/ml) are
similar to the concentration of IL-6 found in prostate cancer tissues
(0 to 53 ng/g) and thus are biologically relevant to this disease
process.
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. The percentage of cells in the S
phase of the cell cycle was similar in treated and untreated cells for
the first 48 hours but decreased markedly in untreated cells after 72
hours when compared to treated controls (Figure 4B)
. Thus the increase
in net cell proliferation in LNCaP cells treated with IL-6 under these
conditions is both because of a decrease in cell death and an increase
in the percentage of dividing cells at later times after treatment.
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To determine whether Stat-3 is phosphorylated in prostate cancer
cells in vivo immunohistochemistry with antibodies to
phospho-Stat-3 was performed on frozen sections of 12 prostate cancer
tissues from radical prostatectomy specimens. Variable nuclear staining
was identified in the prostate cancer epithelial cells in 10 of 12
prostate cancer tissues examined. This varied both between sections and
in different areas of each section. In some cases staining was
extensive and in other cases only focal areas of staining of neoplastic
epithelial cells were seen. An example of extensive staining using
antibodies to phospho-Stat-3 is shown in Figure 5
. Some staining of normal epithelial
cells was seen that was also variable but was less than that seen in
the neoplastic epithelial cells in most cases. Our results are quite
similar to those reported by Campbell and colleagues.17
These investigators also reported significantly higher levels of
phosphorylated Stat-3 in prostate cancer cells compared to benign
prostatic epithelial cells.
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To determine whether IL-6 receptor was increased in human prostate cancer we determined the quantity of IL-6 receptor in protein extracts of 12 human prostate cancer and 4 samples of normal prostate tissue by ELISA. The normal tissue contained 5.4 ± 2.3 (SEM) ng IL-6 receptor per g wet of tissue whereas the cancer tissues contained 44.7 ± 9.5 (SEM) ng per g wet weight. This difference was statistically significant (P < 0.03, t-test). To determine which cells in the benign and malignant prostate express IL-6 receptor we performed immunohistochemistry with anti-IL-6 receptor antibody on six prostate cancers and two normal prostatic tissue samples. In the normal prostate we observed moderate staining of basal epithelial cells and weak staining of the secretory epithelial cells. The stromal cells also expressed moderate levels of IL-6 receptor. Prostate cancer cells expressed variable levels of IL-6 receptor, with some cancers showing intense staining and others having weak or no staining (data not shown). These results are very similar to the results reported by Hobisch and colleagues.13 Therefore the increased levels of IL-6 receptor in prostate cancer tissue are because of increased IL-6 receptor expression in a subset of the prostate cancers.
To determine the biological significance of increased IL-6 receptor
expression in human prostate cancer, we correlated the level of IL-6
receptor expression in the cancers and proliferation, as assessed by
Ki67 immunostaining, in the same cancers using frozen sections obtained
before protein extraction. The cancers were divided into three groups
of four cases each based on the IL-6 receptor protein concentration:
low (mean 12.5 ng/g wet weight), intermediate (38.0 ng/g), and high
(82.5 ng/g). As seen in Figure 6
, the
prostate cancers with high levels of IL-6 receptor expression had
significantly higher rates of proliferation. This difference was
statistically significant by analysis of variance
(P < 0.02). It should be noted that there was
no significant difference between the three groups in the average
Gleason score or in the percent carcinoma in the tissue.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have also demonstrated that normal and neoplastic prostatic epithelial cells in vitro have functional IL-6 receptor complexes that lead to Stat-3 phosphorylation and increased net cell proliferation when cells are treated with IL-6. Thus the increased IL-6 concentration in clinically localized prostate cancer, derived from neoplastic epithelial cells, can then act as an autocrine growth factor for the cancer cells in vivo. The finding that there is increased Stat-3 phosphorylation in vivo in the prostate cancer cells is consistent with the presence of such autocrine growth, although it does not prove it, because Stat-3 can be phosphorylated by activation of other receptors that are expressed in prostate cancer such as the epidermal growth factor receptor.18 However, if Stat-3 phosphorylation had not been seen in vivo, this would have been a strong argument against the existence of autocrine IL-6 activation, so this observation is of significance.
Finally we have shown by ELISA and immunohistochemistry with anti-IL-6 receptor antibody that there is a eightfold increase in IL-6 receptor expression in human prostate cancers because of increased expression of IL-6 receptor by the prostate cancer cells. This increased expression of IL-6 receptors is biologically significant because the cancers with high IL-6 receptor levels have significantly higher rates of proliferation. We did not observe a correlation between increased levels of IL-6 and increased expression of IL-6 receptor. There is obviously the potential for synergism between increased levels of IL-6 and its receptor in promoting proliferation. Indeed, the highest proliferation rate we observed was in a cancer with marked increase in both IL-6 and IL-6 receptor. However, in many cases there was either increased IL-6 or increased IL-6 receptor, so that there seems to be two independent modes of arriving at increased levels of autocrine IL-6 signal transduction in prostate cancer.
The activation of IL-6 receptors in prostate cancer cells has been shown to have a variety of effects in vitro. IL-6 can activate androgen receptor transcriptional activity,11,19 at least in part via Stat-3 phosphorylation.19 It can also lead to increased phosphatidyl-inositol 3' kinase activity, which may have anti-apoptotic effects.20 This is consistent with our finding of decreased cell death in LNCaP cells treated with IL-6. Finally, activation of IL-6 receptors has been shown to lead to activation of erbB2 receptors via a direct physical interaction of this receptor with the gp130 portion of the IL-6 receptor and activation of the mitogen-activated protein kinase pathway.9 Each one of these would be expected to promote net cell proliferation, as we observed in both primary epithelial cell cultures and in the LNCaP cell line. As described previously there has been controversy regarding the effects of IL-6 on LNCaP cells, with some groups observing stimulation of growth,7,9,10 similar to our results, and other groups observing growth inhibition.6,11,12 Whether this represents subtle differences in the conditions in which the growth assays were performed or clonal variation of the LNCaP cell line in different laboratories is unclear.
The role of cytokines in normal prostate biology and prostate cancer is still an emerging area of investigation. IL-6 is present in substantial quantities (100 to 600 pg/ml) in human seminal fluid,8 consistent with the finding that prostatic epithelial cells secrete IL-6 in vitro, although its biological function in the seminal fluid is unknown. Serum IL-6 is significantly elevated in many men with advanced, hormone-independent prostate cancer8,21,22 and elevated IL-6 levels may constitute an independent prognostic marker for decreased survival.22 It has also been suggested that such elevated IL-6 may directly mediate some of the morbidity associated with advanced prostate cancer such as anemia and cachexia.8 Our finding of both increased IL-6 and IL-6 receptor in prostate cancer tissues and the correlation of increased IL-6 receptor with increased proliferation further support the idea that IL-6 may play an important role in prostate cancer progression. Thus disruption of IL-6 autocrine signaling is a potential therapeutic target in prostate cancer. In addition, our results suggest that serum levels of IL-6 soluble receptor, which arises by proteolytic cleavage23 or alternative splicing24 of the IL-6 receptor, may be useful as a prognostic marker either by itself or in conjunction with measurement of serum IL-6 levels.
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Acknowledgements |
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Footnotes |
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Supported by the National Institutes of Health (R01 DK54170) and the Department of Veterans Affairs Merit Review Funding.
Accepted for publication August 29, 2001.
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References |
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