Research Article
The Role of Interleukin-6 and Interleukin-6 Receptor as Prognostic Biomarkers in Prostate Cancer
Tozawa K*, Kawai N, Ando R, Naiki T, Iida K and Yasui T
Department of Nephro-urology, Nagoya City University, Japan
*Corresponding author: Keiichi Tozawa, Department of Nephrourology, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
Published: 21 Oct, 2016
Cite this article as: Tozawa K, Kawai N, Ando R, Naiki
T, Iida K, Yasui T. The Role of
Interleukin-6 and Interleukin-6 Receptor
as Prognostic Biomarkers in Prostate
Cancer. Clin Oncol. 2016; 1: 1124.
Abstract
Background: IL-6 is known to play important roles in the growth of prostate cancer cells, activation
of the androgen receptor and prostate-specific protein expression. It is reported that IL-6 promotes
the growth of prostate cancer. Prostate Specific Antigen (PSA) does not directly assess the biological
behavior of individual hormone-refractory prostate cancers, whereas serum biomarkers produced
by tumors may correlate with disease progression. Prostate cancer cells, especially those that are
hormone-refractory, secrete IL-6. We therefore evaluated the potential of circulating IL-6 levels as a
marker of disease progression. Furthermore, we investigated the correlation with the expression of
IL-6 receptor (IL-6R) and the effects of hormonal therapy against prostate cancer.
Methods: We separated 21 patients with hormonal refractory prostate cancer into one group with
more (higher group; n=9), and another with less (lower group; n=12) serum IL-6 than average. The
correlation between prognosis and serum IL-6 level was investigated in these groups. Furthermore,
in 57 specimens from patients with prostate cancer and benign prostatic hypertrophy, the expression
of IL-6R was examined using immunohistochemistry. The correlation with immunoreactivity of IL-
6R and Gleason grade as well as histological effects of hormonal therapy was compared using the
nonparametric Mann-Whitney U-test and generalized Wilcoxon test.
Results: A comparison of disease-specific survival after PSA failure between these groups
demonstrated that serum PSA and serum IL-6 levels were significantly correlated. The median
survival after PSA failure was significantly shorter in the higher group than in the lower group
(p=0.004). There were significant differences in IL-6R expression between medium Gleason grade
and high Gleason grade (p=0.008), and BPH and high Gleason grade (p=0.004). Furthermore, the
level of IL-6R expression was correlated with the histological effects of hormonal therapy against
prostate cancer.
Conclusion: The serum IL-6 level may be associated with the prognosis of patients with prostate
cancer, and both IL-6 and PSA levels may indicate patients with a poor prognosis. In prostate cancer
patients with strong expression of IL-6R, other therapeutic options without hormonal therapy,
irradiation and/or chemotherapy should be chosen first. The expression of IL-6R may be helpful in
predicting the effects of hormonal therapy against prostate cancer.
Keywords: IL-6; IL-6 receptor; Prostate cancer
Introduction
Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune defense mechanisms and
hematopoiesis, and may also be involved in malignant transformation and tumor progression. A
poor prognosis for patients with multiple myeloma, renal cell carcinoma, ovarian cancer or prostate
cancer is consistently associated with elevated serum IL-6 levels [1-3].
IL-6 induces prostate cancer cell proliferation in vitro through autocrine and paracrine
mechanisms [4]. The serum IL-6 level correlates with lymph nodes and bone metastasis, or
prognosis among patients with hormone-refractory prostate cancer [5]. Furthermore, cross-talk
between IL-6 and the androgen pathway has been demonstrated [6]. Prostate Specific Antigen (PSA)
does not directly assess the biological behavior of individual hormone-refractory prostate cancer,
but serum biomarkers produced by tumors may correlate with disease progression. Prostate cancer
cells, especially those that are hormone-refractory, secrete IL-6.
As IL-6 may be a mediator of morbidity in patients with metastatic disease, we evaluated the
potential of circulating IL-6 levels as a marker of prostate cancer progression.
Furthermore, human prostate cancers and cancer cell lines
almost uniformly expressed the IL-6 receptor (IL-6R) [7,8], giving
rise to an IL-6 autocrine loop.
In this study, immunohistochemical analysis of IL-6R in
hormone refractory prostate cancer was performed. We examined the
correlation with the expression of IL-6R and the effects of hormonal
therapy against prostate cancer.
Figure 1
Figure 1
Serum IL-6 levels compared with PSA in patients with hormone
refractory prostate cancer. Correlation between blood PSA and serum IL-6
level is significant (r2=0.663).
Figure 2
Figure 2
Cancer-specific survival curves of 21 hormone refractory prostate
cancers related to serum IL-6 level. Cancer-specific survival after PSA failure
was significantly longer in the higher level group than in the lower level group
(p = 0.0041).
Figure 3
Figure 3
In three prostate cancer cell lines, positive immunoreactivity of
IL-6R was detected by western blot analysis. The expression of IL-6R in
androgen-independent prostate cancer cells, PC-3 and DU145, was stronger
than in the androgen-responsive prostate cancer cells, LNCaP.
Patients and Methods
Twenty-one patients with hormone-refractory prostate cancer
were selected from Nagoya City University Hospital between October
2011 and September 2013. Levels of IL-6 were determined using an
ELISA and correlation with prognosis and disease-specific survival
after PSA failure was examined. All 21 patients were examined using
X-rays, computed tomography and bone scintigraphy to detect
distant metastasis.
The patients were then separated into one group with more
(higher group; n=9) and another with less (lower group; n=12) than
the average serum IL-6 value, and then we compared disease-specific
survival after PSA failure between the two groups.
Data are presented as means ± Standard Error of the Means
(SEM). Individual groups were compared using the nonparametric
Mann-Whitney U-test, the generalized Wilcoxon test and Student's
t-test. A probability value of p <0.05 was considered significant in all
analyses.
Correlation between IL-6R expression and effects of
hormonal therapy in prostate cancer
Cells and Culture conditions: Cultured human prostate cancer
cell lines, PC-3 and DU145 were obtained from the American Type
Culture Collection (ATCC, USA). The androgen-responsive prostate
cancer cell line, LNCaP was purchased from Dainihon Laboratory
Products Co. (Osaka, Japan). PC-3 and DU145 were maintained in
Eagle's MEM medium supplemented with 10% fetal bovine serum.
LNCaP was maintained in RPMI1640 medium supplemented with
10% fetal bovine serum.
Patients and Samples: Prostatic biopsies from 52 patients who
were diagnosed with prostate cancer and 5 patients diagnosed with
Benign Prostatic Hypertrophy (BPH) at Nagoya City University
Hospital between October 2011 and September 2013 were enrolled in
this study. These patients were subdivided into stage C (8 patients),
stage D (44 patients) and BPH (5 patients) groups according to the
general rules for clinical and pathological studies on prostate cancer.
For the detection of distant metastasis, all the patients were checked by
X-ray, computed tomography and bone scintigraphy. The 52 prostate
cancer specimens were subdivided into three groups by Gleason
grade – low Gleason (dominant grade 1-2), medium Gleason grade
(dominant grade 3) and high Gleason grade (dominant grade 4-5)
(Table 1). The histological criteria of the effects of hormonal therapy
are as follows, Grade 0; the viable cells occupy the entire cancer lesion
in the slice, Grade 1; the non-viable cells are in less than half of the
cancer lesion in the slice, Grade 2; the non-viable cells are in over half
of the cancer lesion in the slice, Grade 3; only non-viable cells are in
the cancer lesion in the slice.
Immunoblotting: Semiconfluent prostate cancer cells were
collected and lysed in modified RIPA buffer (20 mM Tris. HCl [pH
7.4], SDS 0.1%, Triton X 100 1%, sodium deoxycholate 1%). The
protein concentration was determined by BCA assay. After separation
by SDS-PAGE, proteins were transferred to Immobilon-P transfer
membranes (Millipore Co., Bedford, MA). The membranes were
blocked, probed with monoclonal antibody (1:1000) against IL-6R
(Santa Cruz Co., CA, USA) and developed using WESTERN BLOT
KIT (Kirkegaard and Perry Laboratories, Inc., Gaithersburg, MD).
Immunohistochemistry: Paraffin-embedded tissue sections
obtained from 45 patients during the operation were deparafinized
in a cleaning solution (Histochoice, Amresco, OH, USA), rehydrated
in a graded series of ethanol (100%, 95%, 70% and 50%) and washed
in distilled water. Endogenous peroxidase activity was quenched by
1.5% H2O2 in PBS for 15 min followed by washing twice with PBS.
Non-specific protein recognition by the antibody was blocked in
casein wash buffer (containing 0.3% casein and 0.5% Tween20 in
PBS) for 30 min. Tissue sections were then incubated for 1h at room
temperature with the primary antibody, monoclonal anti-IL-6R
antibody. After being washed twice in 1:10 casein wash buffer for 5
min, the sections were incubated with 1:250 biotinylated anti-mouse
IgG (Vector Laboratories, CA) for 30 min. The specific intracellular
immunoreactivity was detected by incubation with avidin-biotin/
horse radish peroxidase complex (Vector Laboratories, CA) for 45
min at room temperature followed by color development in 0.05%
diamino-benzidine/0.01% H2O2/PBS (pH 7.6) chromogen (Sigma,
MO) for 5 min. Color development was stopped by washing in distilled
water, and sections were lightly counterstained in hematoxylin,
dehydrated in a graded series of alcohol, cleared in xylene and finally
mounted in Eukitt.
Semi-quantitative Analysis of IL-6R expression : The degree of
IL-6R expression was estimated and classified into one of five grades
as described previously [9]. Immunoreactivity (IR) of IL-6R was
classified into a scale of 0 to 4 on the basis of tumor cell staining as
follows: 0, no staining; 1, focal, weak staining; 2, strong staining of
<25% of cells or moderate staining of <80%; 3, strong staining of 25
- 50% or moderate staining of >80%; and 4, strong staining of >50%.
The immunostained tissue section slides were examined and scored
independently by two of the authors blinded to any other pathological
or clinical information: in 60% of cases the decisions were consistent,
and the other 40% were reviewed until agreement was achieved.
Statistical Analysis: Data are presented as the mean ± Standard
Error of the Means (SEM). Individual groups (Gleason grade and
histological effects of hormonal therapy) were then compared using
the nonparametric Mann-Whitney U-test, generalized Wilcoxon test
and Student's t-test. For all analyses, a probability value of p<0.05 was
considered significant.
Table 1
Table 2
Figure 4
Figure 4
The positive correlation of IL-6R expression (IR) and Gleason
grade is demonstrated by semi-quantitative evaluation. IL-6R expression
was strongest in prostate cancer patients with a high Gleason grade. There
were significant differences in IL-6R expression between medium Gleason
grade and high Gleason grade (p=0.008), and BPH and high Gleason grade
(p=0.004) by the Mann-Whitney U-test.
Figure 5
Figure 5
The level of IL-6R expression was correlated with the histological
effects of hormonal therapy against prostate cancer. There was a significant
difference in IR of IL-6R between the histological effects of hormonal therapy
grade 1 and grade 3 (p<0.001) by the generalized Wilcoxon test.
Table 3
Results
Table 1 presents the baseline characteristics of the 31 patients
with hormone-refractory prostate cancer. The median age was 74.8
years and 89% of them had bone metastases. The secondary therapy
applied after PSA failure was almost always steroids. Serum PSA and
IL-6 levels significantly correlated (Figure 1).
The mean serum IL-6 value was 4.82 ng/ml (0.8 ~ 79.6 ng/ml).
The median survival after PSA failure in the higher (14.1 months)
group was significantly shorter than that of the lower (35.2 months)
group (p=0.004) (Table 2, Figure 2).
In three prostate cancer cell lines, positive IR of IL-6R was
detected by western blot analysis (Figure 3). The expression of IL-
6R in androgen-independent prostate cancer cells, PC-3 and DU145,
was stronger than in the androgen-responsive prostate cancer cells,
LNCaP. IL-6R expression was detected by immunohistochemistry in
almost all specimens from patients with prostate cancer.
Table 3 presents the baseline characteristics of the 57 patients
with prostate cancer to evaluate IL-6R. In Figure 4, the positive
correlation of semi-quantitative evaluation of the IL-6R expression
(IR) and Gleason grade is demonstrated. IL-6R expression was
strongest in prostate cancer with a high Gleason grade. There were
significant differences in IL-6R expression between medium Gleason
grade and high Gleason grade (p=0.008 Mann-Whitney U-test),
and BPH and high Gleason grade (p=0.004). Interestingly, the level
of IL-6R expression was correlated with the histological effects of
hormonal therapy against prostate cancer (Figure 5). As shown in
Figure 5, we found a significant difference in IR of IL-6R between the
histological effects of hormonal therapy grade 1 and grade 3 (p<0.001
by generalized Wilcoxon test).
Discussion
De Vita et al. [10] demonstrated that IL-6 serum levels are
significantly elevated in patients with advanced gastrointestinal cancer
compared with controls. Moreover, serum IL-6 levels are significantly
higher in patients with disseminated cancer than in those without
apparent metastases. Univariate analysis revealed in the present
study that serum IL-6 levels affected both overall survival and time
to disease progression. As IL-6 signaling can activate the androgen
receptor in a ligand-independent manner, it may play an important
functional role in the progression of hormone-refractory prostate
cancer and in patient survival. Several small studies have associated
plasma and serum IL-6 levels with prostate cancer progression.
The molecular actions of IL-6 in prostate cancer cells have not been
completely elucidated, but IL-6 binds to a trans-membrane receptor
(IL-6Rp80) that requires the association of a second glycoprotein
(gp130) [11]. Signals are then transduced via three possible routes:
the ErbB3(2)-mitogen-activated protein kinase pathway, the
phosphoinositide 3-kinase-Etk/Bmx pathway or the Janus-activated
kinase/signal transducers and activators of transcription pathway,
all of which are associated with androgen-independent prostate
cancer [12]. Recent studies suggest that IL-6R activation represents
a dominant pathway for accessory activation of the androgen
receptor [13]. Furthermore, IL-6 alone is a relatively powerful
activator of androgen receptors in the absence of androgen, and it is
synergistically potent in the presence of low androgen levels [11,12].
Thus, IL-6 functions as an autocrine growth factor for the androgenindependent
growth of prostate cancer cells [1,3]. However, IL-6
may also induce a more differentiated grade of cancer, resulting in
decreased proliferation and apoptosis [14-22]. These studies suggest
that the ultimate cellular effect of IL-6 depends on other genetic and
molecular features of the cancer, including downstream pathways
such as signal transducers and activators of transcription-3, as well
as phosphoinositide 3-kinase. Finally, the dysregulation of IL-6 may
result in paraneoplastic morbidity and early mortality. IL-6 is a potent
mediator of the acute-phase response to injury and infection [11], and
chronically elevated IL-6 levels in Castleman's disease are associated
with a constellation of symptoms that are analogous to those that are
often associated with end-stage prostate cancer [16]. Twillie et al. [22]
have suggested that in patients with advanced hormone-refractory
prostate cancer, serum IL-6 is a prostatic exocrine gene product, a
candidate mediator of prostate cancer morbidity and a potential
marker of disease activity. However, if IL-6 was the sole factor for such
biology, its prognostic significance should more closely correlate with
LDH, performance status and other measures of the host condition.
Serum levels of IL-6 and of IL-6R are typically elevated in
patients with advanced prostate cancer, particularly bone metastases,
and correlate with poor prognosis [23,24]. In the PC-3 and DU145
cell lines, increased activity of the IL-6 promotor has been traced to
constitutive up-regulation of NF-κB and AP-1 transcription factors
[25]. Thus, the constitutive activation of NF-κB, typical of androgenindependent
prostate cancers, may promote androgen independence
via up-regulated IL-6 and STAT3. Pencik et al. [26] reported that
IL6/STAT3/ARF signaling promote progression and metastasis in
prostate cancer. Inhibition of STAT3 signaling may become a target
for advanced prostate cancer [27].
Furthermore, Wegiel B et al. [28] reported that IL6 may utilize
PI3K/Akt and cyclin A1 to promote tumor cell survival in prostate
cancer. Recently, it was demonstrated that autocrine IL6/STAT3
signaling mediates resistance to anti-VEGF therapy in several cancers
[29].
All members of the IL-6 family share the common signal
transduction subunit of their receptors, gp130 [30]. The interaction of
the ligand with its receptor involves binding of the ligand to a specific
receptor component, followed by heterodimerization with the gp130
molecule [31]. In vivo targeting of IL-6 by an anti-IL-6 antibody has
already demonstrated regression of prostate cancer xenografts in
nude mice [32]. In this study, we demonstrated that the expression
of IL-6R in androgen-independent prostate cancer was stronger than
that in androgen-dependent prostate cancer. Furthermore, the level
of IL-6R expression was correlated with the histological effects of
hormonal therapy against prostate cancer. If we speculate the effects
of hormonal therapy against prostate cancer, the appropriate option
of first therapy can be selected. In prostate cancer patients with strong
expression of IL-6R, other therapeutic options, without hormonal
therapy, irradiation and/or chemotherapy, should be chosen first.
We previously analyzed the effects of NF-κB inhibition using
the anti-NF-κB reagent, N-acetyl-L-cysteine (NAC) on the viability
of prostate cancer cells after chemotherapy [33]. We established that
the inhibition of NF-κB activation by NAC substantially enhances the
effects of chemotherapy by CDDP, dosetaxel or etoposide.
We concluded that the expression of IL-6R may be helpful in
predicting the effects of hormonal therapy against prostate cancer.
Furthermore, these results indicate that the serum IL-6 level is
associated with the prognosis of patients with prostate cancer, and
suggest that both IL-6 and PSA are factors that can identify patients
with a poor prognosis who may benefit from more aggressive
management such as with NAC plus CDDP, dosetaxel or Etoposide.
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