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§§§
From the Departments of Oncology,*
Pathology,§
and
Surgery,¶
Kuopio University Hospital; and
the Departments of Anatomy
and Pathology and Forensic
Medicine,
University of Kuopio,
Kuopio, Finland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HA may support tumor growth and spread by regulating cell proliferation1,9 or by enhancing tumor neovascularization through fragmentation into angiogenic oligosaccharides.10 HA likely promotes cell migration by effecting changes in the physical environment so that the accumulation of HA creates expanded gel-filled spaces where cells can migrate.1,11 In addition, HA can, through its cell surface receptors for hyaluronan (HA)-mediated motility (RHAMM) and CD44, give motogenic signals that are mediated, at least in part, by the activation of focal adhesion kinase and mitogen-activated protein kinases.12,13 HA on the cell surface may also increase the probability of metastasis by facilitating the attachment of the disseminating carcinoma cells to lymph nodes or the endothelial cells in distant organs.14
Several lines of evidence indicate that HA metabolism is altered in breast cancer and that this may play an important role in tumor progression. Biochemical15,16 and histochemical17-20 studies have shown that malignant breast tissue contains more HA than normal breast tissue or benign lesions. The stroma at the invading edge of the breast carcinomas is especially enriched in HA.16,17 The stromal fibroblasts stimulated by the tumor cells are probably responsible for most of the HA accumulation in breast tumors.4,5,21,22 However, the most tumorigenic and phenotypically aggressive breast carcinoma cell lines also synthesize large quantities of HA, unlike the less malignant cell lines.6 The invasive potential created by the accumulation of HA may be further aggravated by changes in the expression of HA receptors, CD44 and RHAMM, which both are frequently observed in breast cancer cells.23,24
Despite the extensive evidence for increased HA expression in breast cancer and the general ability of HA to promote experimental tumor progression, no direct relationship between the level of HA accumulation in human breast carcinomas and patient survival rate has been reported. Here we establish a strong correlation between the progression of the disease and the degree of HA accumulation within the peritumoral stroma and cancer cells. These findings are consistent with a causal role of HA in the advancement of human breast carcinoma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The patient material consisted of 143 women operated on for
primary, invasive breast cancer at Kuopio University hospital between
1980 and 1984, and monitored until June 1990. These patients were
selected from the original cohort of 237 patients. In 26 of these cases
either the clinical data or histopathologic samples were not available,
and in 68 cases the histopathologic reevaluation of available samples
did not reveal tumor tissue. The formalin-fixed, paraffin-embedded,
5-µm-thick sections were stained with hematoxylin and eosin for
histological typing and grading. Tumor size was recorded as the largest
diameter in fresh mastectomy specimens. Axillary lymph node status was
studied histopathologically in 93% of patients. The estrogen receptor
(ER) status and progesterone receptor (PR) status were assayed as
previously described.25
ER status was available in 130
(91%) cases and PR status in 132 (92%) cases. The primary treatment
was mastectomy for 139 patients (97%). Postoperative radiotherapy was
given to 67 patients (47%). Adjuvant hormonal therapy and chemotherapy
were given to 24 (17%) and 30 (21%) patients, respectively. The
clinical data of the patients are summarized in Table 1
.
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The biotinylated complex of the hyaluronan-binding region and link protein (bHABC) was prepared from bovine articular cartilage as described previously.26,27 Briefly, the proteoglycans were extracted from the cartilage with 4 mol/L guanidine chloride. The extract was dialyzed against distilled water in the presence of high-molecular-weight hyaluronan. The C terminus of the proteoglycan molecule was cleaved with trypsin, and the resultant complex of hyaluronan-binding region and link protein (HABC) with HA was purified using hydroxylapatite chromatography and gel filtration. The complex was biotinylated, and the bHABC was separated from HA using gel filtration under dissociative conditions. The purity of the preparation was tested by polyacrylamide gel electrophoresis and Western blotting.
Staining of Tissue Sections
The sections were deparaffinized in xylene, rehydrated with graded alcohols, and washed with sodium phosphate buffer (PB; 0.1 mol/L, pH 7.4). Endogenous peroxidase was blocked with 3% H2O2 for 3 minutes, and nonspecific binding was blocked with 1% bovine serum albumin in PB for 30 minutes. The sections were incubated in bHABC (2.5 µg/ml, diluted in 1% bovine serum albumin) overnight at 4°C. The slides were washed with PB and treated with avidin-biotin-peroxidase (Vector Laboratories, Irvine, CA; 1:200 dilution) for 1 hour at room temperature. After the wash with PB, the color was developed with 0.05% 3,3'-diaminobenzidine (Sigma Chemical Co., St. Louis, MO) and 0.03% H2O2 in PB at room temperature for 5 minutes. The slides were counterstained with Mayer’s hematoxylin for 2 minutes, washed, dehydrated, and mounted in DePex.
The specificity of the staining was controlled by digesting some sections with Streptomyces hyaluronidase in the presence of protease inhibitors before staining or preincubating the bHABC probe with hyaluronan oligosaccharides.27
Evaluation of Staining
The sections were examined by a dual-head microscope
simultaneously by two observers (P. A. and V-M. K.). The
level of the stromal HA signal in the invasive areas of breast
carcinoma was graded as weak (no intense HA signal in peritumoral
stroma), moderate (<50% with intense signal), or strong (
50% with
intense signal) and recorded as 1–3, respectively. The expression of
HA in carcinoma cells was graded as negative or positive and recorded
as 0 or 1, respectively. The cell-associated signal was also scored
according to its apparent location in cell surface, cytoplasm, and
nucleus.
Statistical Analysis
The statistics were computed by using the SPSS Base 7.5 for
Windows program package. The relationships between variables were
tested using 
2
analysis. Univariate survival
analyses were based on the Kaplan-Meier method, and the comparisons
between curves were done using the log-rank test. Overall survival
analysis included as an event all deaths, whatever the cause.
Recurrence-free survival was defined as the time elapsed between the
primary treatment and the first recurrence of breast cancer. For
disease-free survival analysis, patients with metastatic disease at the
time of diagnosis were excluded. Multivariate survival analysis was
done by Cox’s proportional hazards model, using the backward method
(removal limit P < 0.10). The variables in
multivariate analysis were tumor size, axillary lymph node status,
primary metastases, histological grade, ER status, PR status, age at
the time of diagnosis, HA expression in tumor stroma, and HA expression
in carcinoma cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. In malignant areas.
the stromal HA staining was generally stronger than in normal stroma
(Figure 1B)
. The intensity of the stromal HA staining varied within
each tumor, but there was no difference in HA expression between the
peripheral or central parts of the tumors. However, the strongest
stromal HA signal always occurred in close proximity to the carcinoma
cells. In the 143 breast carcinomas examined, the intensity of stromal
HA staining was weak in 7 (5%), moderate in 56 (39%) and strong in 80
(56%) cases (Figure 1, C–E)
.
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. In contrast, the breast carcinomas contained
HA-positive epithelial (carcinoma) cells in 81/143 patients (57%). In
most of those cases, the HA-positive cells formed a minority of all
carcinoma cells (5–10%), but in a few cases even 30 to 50% of them
contained HA. The HA in the malignant cells was located on the plasma
membrane in 77/143 (54%) cases (Figure 1F)
, in cytoplasm in 65/143
(45%) cases (Figure 1G)
, and in the nucleus in 21/143 (15%) cases
(Figure 1H)
.
The intensity of the stromal HA signal was associated with the axillary
lymph node positivity (P = 0.015) and poor
differentiation of breast carcinoma (P = 0.003)
(Table 2)
, but not with the other factors
tested, eg, tumor size (P = 0.08), histological
type (P = 0.7), distant metastases
(P = 0.4), ER status (P =
0.7), or PR status (P = 0.2).
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. In addition, the cases with
HA-positive tumor cells were more often ER- and PR-negative
(P = 0.007 and P = 0.001,
respectively) than carcinomas lacking the cell-associated HA
(Table 3)
. The expression of cell-associated HA did not correlate with
tumor size (P = 0.7), histological type
(P = 0.07), or primary metastases
(P = 0.2).
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Both the intensity of the stromal HA signal and the presence of
cell-associated HA related to the overall survival of the 143 breast
cancer patients (Table 4)
. The 5-year
overall survival was 100%, 80%, and 50% with weak, moderate, and
strong stromal HA signal, respectively (P =
0.0001) (Figure 2a)
. The 5-year overall
survival of the patients exhibiting HA-positive carcinoma cells was
54% compared with 81% for the patients without HA-positive carcinoma
cells (P = 0.01; Figure 2b
). In analyses based
on the localization of cell-associated HA, HA on the plasma membrane
correlated with poor 5-year survival (36% for the patients with HA on
the plasma membrane versus 57% for the patients without;
P = 0.02). HA signal in the cytoplasm or in the nucleus
had no prognostic value. The overall survival correlated also with
general indicators like tumor size (P = 0.0001),
axillary lymph node status (P = 0.0001), primary
metastases (P = 0.0001), histological grade
(P = 0.03), and age at diagnosis
(P = 0.0001).
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. The 5-year
disease-free survival of the breast carcinoma patients was 100% with
weak, 73% with moderate, and 49% with strong stromal HA staining
(P = 0.0035; Figure 2c
). The occurrence of
HA-positive carcinoma cells did not associate with disease-free
survival (P = 0.2).
In multivariate analysis the level of the stromal HA signal was a
significant, independent prognostic factor (P =
0.006; Table 5
). The other important
prognostic factors were tumor size (P = 0.0001),
age at diagnosis (P = 0.0006), axillary lymph
node status (P = 0.0007), primary metastases
(P = 0.005), and ER status
(P = 0.01; Table 5
). The multivariate analysis
was done also for a group with both strong stromal HA signal and
carcinoma cell-associated HA (n = 60),
versus others (n = 83). In that
analysis HA expression showed an even stronger predictive power
(P = 0.0009).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Consistent with our results, the cell surface receptors of HA, CD44, and RHAMM have been shown to play a key role in cancer cell adhesion,28,29 cell migration,13 tumor neovascularization,30 and cell signaling in general.24 Also, elevated expressions of CD44 and RHAMM have been linked to breast cancer progression.23,24 Surprisingly, the local content of HA within tumors has received much less attention, even though the abundance of the ligand must be key to processes regulated by the receptors.31 In fact, the present findings on breast cancer and a previous study on colon cancer7 indicate that the level of HA in the malignant epithelium and its immediate vicinity is strongly associated with the spreading status of the tumors and with clinical outcome.
The presence of HA in a fraction of the carcinoma cells and its association with reduced overall survival in univariate analysis indicate that not only the level of surrounding stromal HA but the altered metabolism of HA in the malignant cells themselves promote tumor advancement. The fact that the combination of cell-associated HA with the elevated stromal HA enhanced the predictive power for survival supports the idea that the two parameters act individually but synergistically in promoting tumor spreading.
Although details of the process that leads to accumulation of HA in cancer cells are currently unknown, CD44 variants have been reported to regulate receptor-mediated uptake of HA in cultured breast carcinoma cells.32 In the current study, the cell-associated HA was mostly found on plasma membrane and often in the cytoplasm, but less frequently in the nucleus. The unfavorable prognosis was also most strongly correlated with the cell surface location, suggesting that the intracellular HA may result from uptake mediated by plasma membrane receptors. The abilities of different breast cancer cell lines to bind and internalize HA through CD44 vary; the cell lines with a high binding capacity show the highest invasive potential.32 Our in vivo data strongly support this notion. Cell-associated HA alone was also a very strong indicator of unfavorable prognosis in colon cancer.7
Cell-associated HA, but not matrix-associated HA, was correlated with hormone receptor status. This result complements a previous in vitro work showing that ER- and PR-negative cell lines synthesized and bound more HA than otherwise comparable ER- and PR-positive lines.33 Work in vitro suggests that enhanced synthesis by the cancer cells was also involved in the cellular accumulation of HA.7
The degradation of stromal matrix by metalloproteinases is obviously crucial for the growth and spreading of many malignant tumors.34 Interestingly, HA may stimulate the activity of matrix metalloproteinase 9 in a mouse mammary epithelial carcinoma cell line by a mechanism that involves ligand-induced aggregation of cell surface CD44.35 This suggests a new, direct link between HA accumulation and matrix turnover. HA is not the only new matrix component in the breast cancer stroma, also enriched in versican, an HA-binding proteoglycan,36 and lumican, a small proteoglycan that binds to and modulates the structure of collagen fibers.37 This set of changes in the matrix is apparently effected by the cells on the mesenchymal side, but, perhaps triggered by active oncogenes, such as Ras, in the malignant epithelial cells.38
Tumor size and axillary lymph node involvement are currently the most powerful prognostic factors in breast cancer. Because of the pressure to use less radical operations and neoadjuvant cytostatic therapy, additional prognostic factors like molecular markers are needed to identify the patients that benefit from the most aggressive therapy. The current, relatively simple technique could aid therapeutic decisions based on biopsies taken before the actual operation, because the predictive power of the stromal and cell-associated HA combined was in the same range as that of tumor size and nodal status, the conventional indicators.
The accumulation of HA in malignant cells and adjacent stroma may also offer possibilities for therapeutic interference. Intravenous hyaluronidase, which degrades HA, has been proved relatively nontoxic and has been successfully used to enhance the penetration of cytostatic drugs in bladder carcinomas, squamous carcinomas of neck, and also in breast cancer models.39-41 Agents that specifically inhibit HA synthesis are not currently available, but the recent cloning of the human HA synthase genes42 will facilitate studies on HA synthesis regulation in breast cancer, and provide potential targets of therapeutic interference. For instance, growth factors such as epidermal growth factor and transforming growth factor ß stimulate HA synthesis in certain cells43,44 ; blocking of those growth factors or their receptors could reduce HA synthesis. Down-regulation of RHAMM, the transforming and migration-stimulating receptor of HA, could reduce the effect of excess HA in the vicinity of the malignant cells.45 Antibodies that inhibit the RHAMM function in vitro are available,45 and blocking of HA with soluble peptides that bind HA has been tested in preliminary experiments on animals.46 Furthermore, hyaluronan oligomers inhibit tumor growth in the mouse, presumably by displacing intact hyaluronan from its cell and matrix receptors.47 Therefore, we conclude that further clinical studies on the synthesis and regulation of hyaluronan in malignant tissues are clearly warranted.
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Acknowledgements |
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Footnotes |
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Supported by grants of the Finnish Cancer Union, the Finnish Breast Cancer Group, and Orion Corporation and by EVO funding of Kuopio University Hospital.
Accepted for publication October 6, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gren U, Alhava E, Kosma V-M: Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res 1998, 58:342-347gren U, Parkkinen J, Alhava E, Kosma V-M: Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate. Br J Cancer 1999, 79:1133-1138[Medline]
gren U, Tammi R, Eskelinen M, Kosma V-M: Expression of hyaluronan in benign and malignant breast lesions. Int J Cancer (Pred Oncol) 1997, 74:477-481[Medline]
gren U, Tuhkanen A, Tammi M: Hyaluronan metabolism in skin. Prog Histochem Cytochem 1994, 29:1-77[Medline]
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