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Experimental Therapeutics, Preclinical Pharmacology |
Breast Oncology and Department of Pathology, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113, Japan [T. U., M. T., H. S., M. M., H. B., K. K., M. K.], and Department of Molecular Preventive Medicine, School of Medicine, Tokyo University, Tokyo, Japan [H. I., K. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, IFN-
, IL-8,
macrophage chemoattractant protein (MCP)-1, epithelial-neutrophil
activating peptide-78, vascular endothelial growth factor, and
thymidine phosphorylase (TP) were measured in 151 primary breast cancer
extracts by ELISA. Tumor-associated macrophages (TAMs) were also
examined by immunohistochemistry with anti-CD68 antibodies. The
correlation between soluble mediators and the relationship between TAM
count and soluble mediators were evaluated. MCP-1 concentration was
correlated significantly with the level of vascular endothelial growth
factor, TP, TNF-, and IL-8, which are potent angiogenic factors.
IL-4 concentration was correlated significantly with IL-8 and IL-10. On
the other hand, an inverse association was observed between TP and
IL-12. The level of MCP-1 was associated significantly with TAM
accumulation. In the immunohistochemical analysis, MCP-1 expression was
observed in both infiltrating macrophages and tumor cells. Prognostic
analysis revealed that high expression of MCP-1, as well as of VEGF,
was a significant indicator of early relapse. These findings indicate
that interaction between the immune network system and angiogenesis is
important for progression of human breast cancer, and that MCP-1 may
play an important role in the regulation of angiogenesis and the immune
system. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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T cells play an essential role in the immune reaction to tumors
and have the potential to prevent tumor spread (8)
.
Activated CD4+ T cells differentiate into at least two functionally
distinct subsets, Th1 and Th2 (9)
. The Th1 subset,
stimulated by IL-12, produces IL-2 and IFN-, which activate
cell-mediated immune responses, whereas the Th2 subset produces IL-4,
IL-5, IL-6, IL-10, and IL-13, which encourage humoral immunity
(9, 10, 11)
. Cell-mediated immune responses supported by
Th1-type cells are thought to be optimal in suppression of tumor
development, and tumors are capable of producing several mediators such
as IL-4 and IL-10, which inhibit cell-mediated responses (12
, 13)
. Recent studies indicate that interaction between chemokines
and their receptors is involved in the positioning of T cells
(14)
. For example, MCP-1 has been demonstrated to affect
the differentiation of T cells (15
, 16)
by enhancing IL-4
production in T cells (15)
. Neutralization of MCP-1 by
antibodies resulted in enhanced production of IFN- in T cells on
recognition of the tumor (16)
. These studies suggest that
MCP-1 regulates T-cell development.
Angiogenesis is a multistep cascade involving various soluble mediators. There is increasing evidence to support the important role of the immune system in angiogenesis. TAM content is reported to have a close correlation with microvessel density and prognosis in breast cancer (17, 18, 19) . Notably, the accumulation of TAMs with positive TP is a potent prognostic indicator of early relapse in primary breast cancer (20) . Transfection of tumor cells with the MCP-1 gene promotes angiogenesis in a murine model, and MCP-1 implants induce angiogenesis in rabbit cornea, indicating the important function of MCP-1 in angiogenesis (6 , 21) . IL-4 has a profile as a potent angiogenesis factor (22 , 23) . IL-8, a member of the ELR-CXC chemokine family, was initially identified as a chemoattractant for neutrophils and is now known as a potent endothelial mitogen (24, 25, 26, 27, 28) . ENA-78, a member of the non-ELR-CXC chemokine family, was also reported to be an angiogenic factor (29) . On the other hand, IL-12 has been reported to inhibit angiogenesis through induction of IP-10, which is known to be a negative regulator of angiogenesis (30 , 31) . One of the major angiogenic factors, VEGF, which has been reported to be associated with microvessel density and poor prognosis in various solid tumors, inhibits the development of dendritic cells (32, 33, 34, 35, 36, 37, 38, 39) . These findings indicate that angiogenesis, either directly or indirectly, interacts closely with the immune system and prompted us to investigate the local regulation of these mediators in view of the balance between immune cytokines and angiogenesis factors. In the present study, the local expression of a variety of soluble factors in primary breast cancer tissue was investigated, and their correlation and clinical significance as prognostic factors was determined.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
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Measurement of Cytokines, Chemokines, and Angiogenesis Factors.
The concentrations of cytokines (IL-1, IL-4, IL-6, IL-10, IL-12,
TNF-, and IFN-), chemokines (IL-8, MCP-1, and ENA-78), and
angiogenesis regulators (VEGF and TP) in the tumor extracts were
measured by ELISA (R&D systems, Minneapolis, MN). The measurements were
performed according to the manufacturer’s instructions. The minimal
detection limit for each factor was as follows: IL-1, 0.1 pg/ml; IL-4,
0.13 pg/ml; IL-6, 0.094 pg/ml; IL-10, 0.5 pg/ml; IL-12, 0.5 pg/ml;
TNF-, 0.18 pg/ml; IFN-, 3 pg/ml; IL-8, 10 pg/ml; MCP-1, 5 pg/ml;
and ENA-78, 15 pg/ml. Measurement of VEGF and TP concentrations was
performed as described previously (40)
. Briefly, VEGF
concentrations were measured by a colorimetric ELISA using a polyclonal
antibody to human VEGF121 (091895; Toagosei, Ibaraki, Japan), which
reacts specifically with the soluble isoforms of the peptide. The
minimal detectable level was 5 pg/mg protein. TP levels were also
determined by a colorimetric ELISA. This sandwich immunoassay used two
antihuman TP monoclonal antibodies (Nippon Roche Research Center,
Kamakura, Japan; 104B and 232-2). The minimal detectable concentration
was 2 units/mg. One unit of TP is equivalent to the enzymatic activity
that generates 1 ng of 5-fluorouracil from 5-deoxy-5-fluorouridine/h.
The numbers of cases examined are listed in Table 2
.
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Immunohistochemistry of TAM and MCP-1.
TAM count was determined for 50 of the 151 cases. Sections (3–5
µm) of paraffin-embedded tumor tissues were used in an indirect
anti-peroxidase immunohistochemical assay (Dako, Carpinteria, CA). TAMs
were stained with an anti-CD68 monoclonal antibody (PG-M1; Dako A/S,
Copenhagen, Denmark), and positively stained cells were counted by eye
in the five most confluent microscopic fields (per
mm2
; Ref. 20
). The mean count was
determined from the highest three counts of the five and considered as
the TAM count. MCP-1 expression was examined by the same indirect
immunohistochemical method using an anti-MCP-1 monoclonal antibody as
described previously (41)
.
Adjuvant Therapy and Patient Follow-Up.
The schedule for adjuvant treatment was based on each patient’s
individual characteristics including axillary node involvement, tumor
size, age, and ER. Poly-chemotherapy including six cycles of
cyclophosphamide, Adriamycin/epirubicin, and FU was given to
node-positive patients under the age of 55, and FU derivatives were
given to the other remaining node-positive and high-risk node-negative
patients. Tamoxifen was given to hormone receptor-positive patients for
at least 2 years (5 years to node-positive patients). The patients were
followed-up every 3 months, and recurrence was confirmed by
histological examination or image examination.
Statistical Analysis.
The correlation between two factors was evaluated by the Spearman’s
rank correlation coefficient. Unpaired groups were compared by the
Student’s t test. Kaplan-Meier survival curves were
plotted, and the difference in prognosis between the two groups was
analyzed by the log-rank test. Multivariate analyses were performed
using the Cox proportional hazards model. P < 0.05 was
considered to indicate statistical significance.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Only two cases had measurable levels of IFN-, and this
factor was therefore excluded from the analysis. A significant
correlation between axillary node status and the level of IL-4 was
detected. The level of IL-4 was significantly higher in node-positive
than in node-negative patients (P = 0.012). However,
other molecules were not associated with node status.
Relationship between Macrophage Accumulation and Soluble Mediators.
TAM counts varied from 5 to 480 counts/mm2
(median, 125 counts/mm2
). The levels of MCP-1 and
TP were correlated significantly with macrophage accumulation
(P = 0.0197 and P = 0.036,
respectively; Table 3
). The levels of TNF- and IL-8 also tended to be correlated with TAM
counts (P = 0.0514 and P = 0.095,
respectively).
|
. Expression of MCP-1 had a significant positive correlation with
expression of VEGF, TP, TNF-, and IL-8 (P = 0.0003,
P < 0.0001, P < 0.0001, and
P = 0.007, respectively) and had a similar relationship
with expression of IL-6 and IL-10 (P = 0.0584 and
P = 0.0747, respectively). Expression of VEGF was also
found to be positively associated with expression of TP, TNF-, and
IL-6 (P = 0.0004, P = 0.0002, and
P = 0.012, respectively). TP expression was associated
significantly with the expression of TNF- and IL-1
(P < 0.0001 and P < 0.0001,
respectively). Among the cytokines, IL-4 expression was strongly
correlated with expression of IL-8 and IL-10 (P =
0.0069 and P = 0.0005, respectively). An inverse
association was observed between TP and IL-12 (P =
0.0266).
|
. Monocytic cells were major components of the stromal cells that
expressed MCP-1, but some fibroblastic spindle-shaped cells were also
positive for MCP-1 staining.
|
). All variables with P < 0.2 in the univariate
analysis were included in the multivariate analysis. VEGF and MCP-1
were assessed as a combined phenotype because of a close interfactorial
correlation. A combined VEGF and MCP-1 status had an independent
prognostic significance after node status and ER status
(P = 0.0356; Table 6
; Fig. 2
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A number of studies have revealed the relationship between
angiogenesis and the immune system. Several cytokines including
TNF-, IL-1, and IFN- are known to be inducers of TP (46
, 47)
. In fact the close correlation between TP and TNF-, and
between TP and IL-1, was confirmed in this study. MCP-1 is known to be
a regulator of T-cell differentiation. In particular, MCP-1 induces Th2
cytokine IL-4, whereas it inhibits generation of Th1-type cells,
suggesting that MCP-1 might induce Th2 dominance in tumor surroundings
(15
, 16) . Our results failed to demonstrate a direct
correlation between MCP-1 and Th2 cytokines but showed that MCP-1
levels tended to be associated with IL-6 and IL-10. It was also
observed that Th2-type cytokines, including IL-4 and IL-10, were
correlated with each other in breast tumors. The lack of correlation
between MCP-1 and IL-4 might be attributable to the fact that IL-4 is
derived not only from lymphocytes but also from other types of cells
such as mast cells (22
, 23)
.
IL-12 and IFN-, both of which are Th1 cytokines, have been
shown to inhibit angiogenesis (30
, 31
, 48, 49, 50, 51)
. In this
study, VEGF correlated with the Th2 cytokine IL-6, and TP had an
inverse correlation with the Th1 cytokine IL-12, suggesting that
angiogenic factors might be regulated cooperatively with Th2 cytokines
in tumor surroundings. Indeed, it has been reported that VEGF has an
inhibitory effect on the differentiation of dendritic cells (36
, 52)
. In lung cancer, it has also been noted that the Th2-type
immune stage is dominant rather than the Th1-type stage, which implies
that evasion of Th1-dominant status might be crucial for tumor cells to
grow (53)
.
The prognostic analysis showed that MCP-1, as well as VEGF, was a significant prognostic indicator. In the multivariate analysis, a combined MCP-1 and VEGF status was an independent prognostic indicator. The immune-regulating function and angiogenic function of MCP-1 might contribute to the poor prognosis of breast cancer patients with high MCP-1 levels. Because the prognostic significance of VEGF has been confirmed in various tumors, further assessment of the prognostic value of MCP-1 is warranted.
In conclusion, this study showed that MCP-1 expression was associated with macrophage accumulation and correlated with the concentration of various angiogenic regulators, and that MCP-1/VEGF was an independent prognostic indicator in breast cancer. MCP-1 might be a candidate for regulation of the relationship between angiogenesis and the immune balance in human breast carcinoma. MCP-1 could be a novel target in cancer treatment once its role in immune regulation and angiogenesis is better understood.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Tokyo Metropolitan Komagome Hospital, 3-18-22,
Honkomagome, Bunkyo-ku, Tokyo 113, Japan. Phone: 81-3-3823-2101; Fax:
81--3-3824-1552; E-mail: maktoi77{at}wa2.so-net.ne.jp 
2 The abbreviations used are: TAM,
tumor-associated macrophage; MCP-1, macrophage chemoattractant
protein-1; Th1 and Th2, T helper 1 and 2, respectively; VEGF, vascular
endothelial growth factor; TP, thymidine phosphorylase; IL,
interleukin; TNF, tumor necrosis factor; ENA-78, epithelial-neutrophil
activating peptide-78; IP-10, IFN- inducible protein-10; ER,
estrogen receptor; PgR, progesterone receptor; FU,
5-fluorouracil.
Received 1/ 4/00; revised 5/19/00; accepted 5/22/00.
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M. Wolf, I. Clark-Lewis, C. Buri, H. Langen, M. Lis, and L. Mazzucchelli Cathepsin D Specifically Cleaves the Chemokines Macrophage Inflammatory Protein-1{alpha}, Macrophage Inflammatory Protein-1{beta}, and SLC That Are Expressed in Human Breast Cancer Am. J. Pathol., April 1, 2003; 162(4): 1183 - 1190. [Abstract] [Full Text] [PDF]
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J. J.W. Chen, P.-L. Yao, A. Yuan, T.-M. Hong, C.-T. Shun, M.-L. Kuo, Y.-C. Lee, and P.-C. Yang Up-Regulation of Tumor Interleukin-8 Expression by Infiltrating Macrophages: Its Correlation with Tumor Angiogenesis and Patient Survival in Non-Small Cell Lung Cancer Clin. Cancer Res., February 1, 2003; 9(2): 729 - 737. [Abstract] [Full Text] [PDF]
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E. Barbera-Guillem, J. K. Nyhus, C. C. Wolford, C. R. Friece, and J. W. Sampsel Vascular Endothelial Growth Factor Secretion by Tumor-infiltrating Macrophages Essentially Supports Tumor Angiogenesis, and IgG Immune Complexes Potentiate the Process Cancer Res., December 1, 2002; 62(23): 7042 - 7049. [Abstract] [Full Text] [PDF]
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R. Huang, Y. Lin, C. C. Wang, J. Gano, B. Lin, Q. Shi, A. Boynton, J. Burke, and R.-P. Huang Connexin 43 Suppresses Human Glioblastoma Cell Growth by Down-Regulation of Monocyte Chemotactic Protein 1, as Discovered Using Protein Array Technology Cancer Res., May 1, 2002; 62(10): 2806 - 2812. [Abstract] [Full Text] [PDF]
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E. Azenshtein, G. Luboshits, S. Shina, E. Neumark, D. Shahbazian, M. Weil, N. Wigler, I. Keydar, and A. Ben-Baruch The CC Chemokine RANTES in Breast Carcinoma Progression: Regulation of Expression and Potential Mechanisms of Promalignant Activity Cancer Res., February 1, 2002; 62(4): 1093 - 1102. [Abstract] [Full Text] [PDF]
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M. C. A. Duyndam, M. C. G. W. Hilhorst, H. M. M. Schluper, H. M. W. Verheul, P. J. van Diest, G. Kraal, H. M. Pinedo, and E. Boven Vascular Endothelial Growth Factor-165 Overexpression Stimulates Angiogenesis and Induces Cyst Formation and Macrophage Infiltration in Human Ovarian Cancer Xenografts Am. J. Pathol., February 1, 2002; 160(2): 537 - 548. [Abstract] [Full Text] [PDF]
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