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Tumor Biology |
Scott Department of Urology [S. S., G. Y., S. E., A. F., T. C. T.] and Departments of Pathology [T. M. W.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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I), including
TAMs/mm2 total tumor tissue
(MItotal),
TAMs/mm2 tumor stroma
(MIstroma),
and TAMs/mm2 cancer cell area
(MIcancer).
MIs were analyzed in association with patients’
clinical and pathological stage, recurrence status, and histological
grade of the cancer. There were significant inverse relationships
between
MItotal
and
MIstroma
and clinical stage (P = 0.016 and
P = 0.006, respectively). Reduced
MItotal
was also associated with the presence of positive lymph nodes
(P = 0.010). Interestingly, although all
of the MIs differed between Gleason score groups, only
MIcancer
was positively associated with Gleason score. Univariate analysis of
MItotal
and multivariate analysis of
MItotal
with specific pathological markers revealed that
MItotal
was an independent predictor for disease-free survival after surgery
(Cox proportional hazard model, P = 0.044
and P = 0.007, respectively). For
patients with high
MItotal
(
185.8, the mean
MItotal
value), the disease-free probability 5 years after surgery was 0.75,
which was significantly higher than for those with low
MItotal
(0.31, P = 0.0008). Additional
immunohistochemical studies that evaluated cytotoxicity-related
biomarkers in stroma-associated mononuclear cells suggested reduced
functional activities in highly aggressive prostate cancer compared
with less aggressive disease. Our results indicate that reduced
MItotal
is a novel prognostic marker for prostate cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, prostaglandins, and insulin-like
growth factor I (reviewed in Ref. 4
). Under some
conditions, these growth factors have the capacity to stimulate tumor
cell growth and/or survival directly and in some cases may promote
tumorigenesis indirectly through the induction of tumor vasculature
(4, 5, 6)
. TAMs are also capable of producing tumor
cytotoxicity directly through the production of TNF-
(7, 8, 9)
, NO (8
, 10
, 11)
,
H2O2 (12)
, and
reactive oxygen intermediates and indirectly through the secretion of
cytokines such as IL-12 and IL-18 to stimulate the immune system. In
some cases, TAMs appear to function as antigen-presenting cells to
further promote antitumor immunity (3
, 13)
. Although TAMs
have the potential to mediate tumor cytotoxicity and to stimulate
antitumor lymphocytes (7)
, these activities can be
suppressed by tumor-derived cytokines that include IL-4, -6, -10,
TGF-ß1 (14
, 15)
, prostaglandin E2
(16)
, and macrophage colony-stimulating factor
(17)
. TAMs have also been shown to produce and secrete
specific proteases, including urokinase plasminogen activator that can
have profound effects on tumor cell activities (14
, 18)
.
The overall complexity of TAM-related biological activities presents a
challenging scenario from which to determine the clinical significance
of TAMs for specific malignancies. The results of various immunohistochemical staining analyses using macrophage-specific markers have not led to general consensus regarding the prognostic significance of TAMs. In papillary thyroid cancer, patients with tumors containing TAMs exhibiting neoplastic cell phagocytotic activities had a better prognosis than patients without TAMs (19) . In contrast, the presence of areas of high-density TAMs within "hot spots" was positively correlated with increased vascularity and metastasis and with reduced relapse-free and overall survival in breast cancer (6) .
In the present study we performed quantitative immunohistochemical
analysis of TAMs in human prostate cancer tissues using a CD68
monoclonal antibody. We expressed the data as
MI, i.e.,
TAMs/mm2 total tumor tissue
(MItotal);
TAMs/mm2 tumor stroma
(MIstroma);
and TAMs/mm2 cancer cell area
(MIcancer).
Inverse associations between both
MItotal
and
MIstroma
and clinical indicators of disease progression were revealed.
MItotal
was further shown to be an independent predictor for time to disease
progression after radical prostatectomy. Interestingly, a positive
association was demonstrated between
MIcancer
and Gleason score. Overall, our results clearly demonstrate novel
prognostic capacity of reduced TAMs in prostate cancer tissues and
reveal the importance of the local tumor microenvironment in regard to
the biological and clinical impact of TAMs in prostate cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunohistochemistry.
Six-µm-thick sections were made from the tissue blocks fixed in 10%
formalin and embedded in paraffin after a routine procedure. The
sections were deparaffined and rehydrated. They were then heated in
citrate buffer (0.01 M, pH 6.0) with in an 800 W microwave
oven for 9 min for antigen retrieval. Endogenous peroxidase in sections
was inactivated in 2% H2O2
for 10 min. The sections were then blocked in 3% normal horse serum in
0.2 M PBS (pH 7.4), followed by incubation in monoclonal
antibody specific for human CD68 (Dako Corp., Carpinteria, CA). The
CD68 antibody was used at a dilution of 1:200 in PBS with 0.5% normal
horse serum. The sections were incubated in the primary antibody for
2 h at room temperature and then processed after standard ABC
immunostaining procedures with an ABC kit (Vector Laboratories,
Burlingame, CA). Immunoreaction products were visualized in a
3,3'-diaminobenzidine/H2O2
solution. To verify the specificity of the immunoreactions, some
sections were incubated in normal mouse serum replacing primary
antibody. In addition, antibodies to NOS2, TNF-, and TGF-ß1
(from Santa Cruz) were also used to immunostain some paraffin-embedded
(for NOS2 and TGF-ß1) or frozen (for TNF) sections of some tumors,
using the ABC technique.
Histological Analysis.
TAMs were quantified by systematically screening the entire cancer area
and by counting at the hot spot in a cancer area where
macrophages accumulated at highest density in the specimens.
For systematic counting, 10 to 15 ocular measuring fields, each
composed of 100 grids and having a real area of 0.0625
mm2, were randomly chosen under a microscope at a
power of x400 within a cancer. Sections were positioned such that each
measuring field was completely occupied by only cancer tissue. All TAMs
in each measuring field were counted and stratified as those localized
to cancer stroma and those in contact with cancer cells or penetrating
into a cancer lumen. The grids in each measuring field were also
stratified by percentage into the two compartments: tumor stroma area
or cancer cell/lumen area. The counts of
MItotal,
MIstroma,
MIcancer,
and
MIbenign
were recorded for each specimen. For counting macrophages in hot spots,
the sections were first evaluated at x100, and the cancer area where
TAMs accumulated at higher density was identified. TAMs were then
counted at x400 within the hot spot and expressed as
MIhot
spot. All counting was performed by one investigator
(S. S.) without knowledge of clinical information. In addition, NOS2-,
TNF--, and TGF-ß1-positive tumor-infiltrating mononuclear cells
were also scored separately on tissue sections. For each specimen, the
whole cancer area was screened under a microscope at x200, and
positively labeled mononuclear cells were counted from 10 to 20
randomly selected microscopic fields. The densities of these cells were
scored as follows: -, no mononuclear cell was labeled; +, 
1 positive
cell per microscopic field; ++, >1 and <5/field; and +++, 5/field.
NOS2, TNF--, and TGF-ß1-positive cancer cells were scored
according to their relative densities as +, low; ++, moderate;
and +++, high.
Statistical Analysis.
The association of MIs with patients’
clinical stage and Gleason score was evaluated using Kruskal-Wallis
test. The association of MIs with extraprostatic
extension, seminal vesicle invasion, lymph node metastasis, and
surgical margin was evaluated using the Mann-Whitney test. The
Mann-Whitney test was also used to evaluate the difference in
MItotal
between benign and malignant cancer patients. Univariate analyses of
MIs as a continuous variable and the
postoperative pathological markers as well as multivariate analyses of
MIs adjusting for pathological markers were
performed using the Cox proportional hazard regression model. Survival
curves of relapse-free survival for high- and
low-MItotal
patients were obtained using a Kaplan-Meier analysis and tested with
log-rank test. Cox proportional hazard regression model was used to
evaluate the difference between these survival curves, adjusting for
pathological markers. Associations between tumor histology and
immunoreactivity for NOS2, TNF-, and TGF-ß1 were tested using
Fisher’s exact test. The frequency of positive cancer cells between
the more and less aggressive cancers was grouped and compared as + versus ++/+++. P < 0.05
was considered statistically significant in all of the analyses. All
analyses were performed with statistical software (StatView version
5.0, SAS Institute Inc., Cary, NC and/or SPSS 10.0, SPSS Inc., Chicago,
IL).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
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. The remaining, smaller proportion of TAMs (16%) was in
direct contact with cancer cells or penetrated into the lumens
of cancer cells (Fig. 1C)
. This ratio varied with the
Gleason grade in individual cancer specimens. As expected, cancers of
lower grade (Gleason score, 6) had a larger proportion of
cancer stroma than cancers of higher Gleason grade, and this increased
stroma-cancer cell ratio contributed to an increased number of
stroma-infiltrating TAMs. Overall, the macrophage density,
i.e.,
MItotal,
was significantly higher in the malignant/total tumor tissue area
(185.8.1 ± 11.8, mean ± SEM;
n = 81) relative to adjacent histologically
benign prostatic areas (84.1 ± 16.4;
n = 10, P = 0.0012;
Fig. 2
).
|
Is with Clinical and
Pathological Characteristics.Itotal,
MIstroma,
and
MIcancer,
were determined and tested for associations with clinical stage,
Gleason score, and other pathological parameters (Table 1)
. Patients with cancers of relatively high TNM stage tended to
have a lower
MItotal
and
MIstroma.
Both
MItotal
and
MIstroma
were inversely associated with TNM stage (P = 0.016 and P = 0.006, respectively). An
inverse association was also found between the
MIhot
spot (see "Materials and Methods") and clinical stage
(P = 0.012; Table 2
). All MIs were significantly different between
Gleason score patient groups, although only
MIcancer
showed a trend for positive association with the Gleason score
(P = 0.006). A significantly lower
MItotal
was detected in patients with positive lymph node metastasis
(P = 0.010). There was no statistically
significant association between any specific
MI and the status of the surgical margins,
extraprostatic extension, or seminal vesicle invasion.
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Itotal
as a Predictor for Disease-free Survival.Is and the
recurrence in this set of patients were also analyzed using the Cox
proportional hazard model. As continuous variables,
MItotal,
MIstroma,
MIcancer,
and MIhot spot as well as other
pathological markers were first univariately analyzed for predictive
value. The results revealed that the following were significant
predictors of time to recurrence:
MItotal,
MIcancer,
extraprostatic extension, seminal vesicle invasion, lymph node
metastasis, surgical margin status, and Gleason score (Table 3)
. However, when
MItotal,
MIstroma,
MIcancer,
and MIhot
spot were individually combined with the pathological
markers in four separate models for multivariate analysis, in the
reduced prediction models only
MItotal
remained a significant predictor of time to recurrence in the presence
of the surgical margin status and Gleason score (Table 4)
.
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Itotal.Itotal
was then tested using a Kaplan-Meier actuarial analysis (Fig. 3)
. The follow-up time ranged from 0.8 to 131.7 months (mean, 46.6
months). Forty-two (52%) of 81 patients had biological recurrences
(PSA 0.4 ng/ml) during follow-up. The
MItotal
values for this set of patients averaged 185.8. When using this mean as
a cutoff point, 47 cases (58%) were in the low category (<185.8),
with 34 cases (42%) falling into the high (185.8) category. The
recurrence-free probability (disease-free survival) at 60 months in the
high-MItotal
category (0.75) was significantly higher than that in the
low-MItotal
group (0.31, P = 0.0008; Fig. 3
). The mean
recurrence-free survival time for the
high-MItotal
category was 96.10 months (95% confidence interval, 78.0–114.2),
whereas the
low-MItotal
category was 52.2 months (95% confidence interval, 36.7–67.6). The
predictive value of the high- versus the
low-MItotal
remained significant (P = 0.002) in presence
of the surgical margin status and Gleason score, used in the
multivariate Cox proportional hazard model.
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-, and
TGF-ß1-positive Mononuclear Cells in Prostate Cancer., and TGF-ß1 expression are related to
macrophage function, we investigated these activities in mononuclear
cells using semiquantitative immunohistochemical analysis and compared
well-differentiated cancers from nonrecurrent patients with poorly
differentiated cancers from recurrent patients. Overall, the majority
of positively labeled cells for each antigen demonstrated macrophage
morphology. In the less aggressive cancers, tumor-infiltrating,
NOS2-positive mononuclear cells were mainly localized to the stroma of
a cancer (Table 5)
, and their density was significantly lower in the more aggressive
cancers (P = 0.001). Compared with the less
aggressive cancers, significantly increased densities of NOS2-positive
mononuclear cells in close contact with cancer cells
(P = 0.001) were observed in the aggressive
cancers. Densities of NOS2-positive cancer cells per se
within highly aggressive prostate cancer were significantly increased
compared with less aggressive prostate cancer (P = 0.001). Significantly fewer TNF--positive mononuclear cells
were observed in the stroma of highly aggressive cancers compared with
the less aggressive ones (P = 0.021), but
there was no difference in the densities of TNF--positive
mononuclear cells in close contact with cancer cells between the two
groups (P = 0.354). In the highly aggressive
cancers, the densities of cancer cells positive for TNF- staining
appeared to be increased relative to the less aggressive cancers, but
no statistically significant difference was detected
(P = 0.308). There were similar densities of
TGF-ß1-positive mononuclear cells infiltrating in the cancer stroma
and in close contact with cancer cells in the two groups, but the
frequency of TGF-ß1-positive cancer cells was significantly increased
in the highly aggressive cancers compared with the less aggressive ones
(P = 0.005).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Itotal)
or within the tumor stroma
(MIstroma)
is inversely associated with clinical stage.
MItotal
was also inversely associated with the presence of positive lymph
nodes. We additionally analyzed
MItotal
in regard to its capacity to predict the time to recurrence as
estimated by biochemical recurrence, i.e., rising serum PSA,
after radical prostatectomy using both univariate and multivariate
analyses. The results indicated that reduced
MItotal
is an independent predictor for time to disease progression.
Interestingly, we also found that TAM density within the cancer cell
area, i.e.,
MIcancer,
was positively associated with the Gleason score. In general, our
results establish that reduced
MItotal
is a novel prognostic marker for prostate cancer progression and that
the compartmental localization of TAMs may determine their specific
role in prostate cancer progression.
In other tumor systems, the presence of increased lymphocytes
within the cancer cell area indicates a favorable prognosis. For
example, CD8+ T cells infiltrated within human
colorectal cancer have a positive prognostic significance in regard to
patient survival (21)
. However, in our study
MIcancer
was positively associated with Gleason score, a well-established and
useful pathological marker of progression. Leek et al. have
reported previously that increased presence of macrophages correlates
with tumor growth and metastasis in breast cancer (6)
. In
their report, a significant positive correlation between high vascular
grade and increased macrophage index and a strong relationship between
macrophage index and reduced relapse-free survival and reduced overall
survival were observed. This article used the technique of counting
macrophages within hot spot areas within the tumor that are not
specified in regard to cellular compartment. In this report, we also
used hot spot counting in addition to systematic counting for TAMs.
Unlike the results obtained using the systematic counting protocol, the
results from hot spot counting, i.e.,
MIhot
spot, did not show any prognostic significance, but, in
general, they were consistent with the results of the systematic
counting protocol that demonstrated an inverse association of
MItotal
and
MIstroma
with clinical stage.
Overall, the results of this study and studies from other laboratories indicate that the cellular microenvironment is critical in determining the biological and clinical significance of specific tumor-associated immunocytes. However, our study also specifies that TAMs within the cancer stroma versus cancer cell compartments may have opposing activities in regard to their effects on cancer progression.
As observed in this study, some of the mononuclear cells in the
cancer stroma express NOS2 and TNF-, which can contribute either
indirectly or directly to tumor cell cytotoxicity. The majority of
these cells demonstrated macrophage morphology. The frequency of NOS2-
and TNF-positive mononuclear cells was reduced within the cancer
stroma in poorly differentiated nonrecurrent prostate cancer compared
with differentiated recurrent prostate cancer. In contrast, the
densities of NOS2-positive mononuclear cells in contact with the cancer
cells in the highly aggressive prostate cancer were increased compared
with the less aggressive prostate cancer. Furthermore, significant
increases in NOS2- and TGF-ß1-positive prostate cancer cells
per se were also demonstrated in highly aggressive prostate
cancer versus less aggressive disease. The reduction in the
densities of NOS2- and TNF-positive mononuclear cells that
infiltrate the stroma in highly aggressive prostate cancers compared
with less aggressive disease suggests that the cytotoxic activities of
these cells become attenuated during the acquisition of increasing
malignant potential of the cancer. The reduced densities of NOS2- and
TNF--positive mononuclear cells in the cancer stroma does not appear
to simply reflect an overall reduction of macrophage density in this
compartment, because macrophage densities in high Gleason grade cancers
increased relative to low Gleason grade cancers (see Table 1
).
Interestingly, in prostate cancer as in many other malignancies, an
overall reduction in tumor stroma specifies a more malignant
pathological grade. It is conceivable that an overall reduction in
specific stromal cells within high-grade lesions lead to reduced
potential for specific stromal cell-mononuclear cell interactions that
are supportive of antitumor cytotoxic activities. In this regard, our
previous studies have demonstrated that the genetic background of
prostate stromal cells specifically can dramatically affect the
incidence of prostate carcinogenesis in vivo using the mouse
prostate reconstitution model system (22)
. The increased
densities of NOS2-positive mononuclear cells in contact with cancer
cells and cancer cells per se as well as TGF-ß1-positive
cancer cells in highly aggressive prostate cancers relative to less
aggressive disease suggest selection for resistance to the
cytotoxic/growth-suppressive effects of NOS2 and TGF-ß1 activities.
Indeed, previous studies have indicated that various malignant cells
can overexpress NOS2 (reviewed in Refs. 23
and
24
), and in particular, TGF-ß1 has been associated with
prostate cancer progression (25
, 26)
. The role of prostate
cancer stroma in regard to support of immunocyte-mediated cytotoxic
activities is deserving of additional studies based on this report and
other observations. In addition, the inverse association between
MItotal
and disease-free survival after radical prostatectomy is also deserving
of further study, which could provide more insight into prostate
cancer progression and potentially establish macrophage density as a
clinically useful prognostic marker.
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FOOTNOTES |
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1 Supported by National Cancer Institute Grant
CA50588 and Specialized Program of Research Excellence
P50–58204. 
2 To whom requests for reprints should be
addressed, at Scott Department of Urology, Baylor College of Medicine,
6560 Fannin, Suite 2100, Houston, TX 77030. Phone: (713) 799-8718;
Fax: (713) 794-7983; E-mail: timothyt{at}www.urol.bcm.tmc.edu
3 The abbreviations used are: TAM,
tumor-associated macrophage; IL, interleukin; TGF-ß1, transforming
growth factor ß1; TNF, tumor necrosis factor; MI,
macrophage index; TNM, tumor-node-metastasis; PSA, prostate-specific
antigen; NOS2, nitric oxide synthase 2; ABC, avidin biotin complex.
Received 11/29/99. Accepted 8/18/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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production. J. Immunol., 153: 1674-1686, 1994.[Abstract]
molecules and inhibits tumor-specific T cell- and natural killer cell-mediated cytotoxicity. Eur. J. Immunol., 26: 1308-1313, 1996.[Medline]
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 A. Y. Liu and L. D. True Characterization of Prostate Cell Types by CD Cell Surface Molecules Am. J. Pathol., January 1, 2002; 160(1): 37 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mercader, B. K. Bodner, M. T. Moser, P. S. Kwon, E. S. Y. Park, R. G. Manecke, T. M. Ellis, E. M. Wojcik, D. Yang, R. C. Flanigan, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer PNAS, December 4, 2001; 98(25): 14565 - 14570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schumacher, W. Haensch, C. Röefzaad, and P. M. Schlag Prognostic Significance of Activated CD8+ T Cell Infiltrations within Esophageal Carcinomas Cancer Res., May 1, 2001; 61(10): 3932 - 3936. [Abstract] [Full Text]
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