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Tumor Biology |
Departments of Obstetrics and Gynecology [M. A. A., S. V. S.] and Clinical Pathology [V-M. K.], Kuopio University Hospital, and Departments of Anatomy [R. H. T., M. I. T.] and Pathology and Forensic Medicine [M. A. A., K. J. S., V-M. K.], University of Kuopio, FIN-70211 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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Hyaluronan is an extracellular polysaccharide (4) typically present in the extracellular matrix of some epithelial and neural tissues and is particularly abundant in connective tissues. Hyaluronan controls cell migration, differentiation, and proliferation (5) , thereby influencing tissue morphogenesis, wound healing, and tumor growth (6 , 7) . Earlier in vitro studies have indicated that the hyaluronan levels correlate with the invasive and metastatic capacity of the tumor cells (8 , 9) . Increased hyaluronan concentrations may help invasion by providing a less dense matrix for cancer cells (10) , stimulating cancer cell motility (11) and forming an immunoprotective coat for cancer cells (12) . In addition, the cell surface receptors of hyaluronan, i.e., CD44 and RHAMM, have been shown to play a key role in cancer cell adhesion (13) , cell migration (14) , and tumor neovascularization (15) .
Interestingly, in vitro studies have indicated that the standard form of CD44 protein is needed for human ovarian cancer cell binding to mesothelial hyaluronan (16, 17, 18, 19) . Moreover, anti-CD44 antibodies have been shown to prevent the peritoneal spreading of ovarian tumor cells in a mouse model (20) . Human ovarian cancers express both the standard and different variant isoforms of CD44, but their prognostic significance remains ambiguous (21 , 22) .
Despite widespread interest in the role of CD44 in ovarian cancer, the content of hyaluronan, its major ligand, has not received any attention. Therefore, we evaluated hyaluronan levels and their relation to CD44 expression, tumor progression, and patient survival in a representative series of epithelial ovarian cancers.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tumor staging was based on the standards of the
FIGO3
(23)
. In addition to postoperative adjuvant chemotherapy,
9 patients received postoperative radiotherapy, and 38 patients
received both of these adjuvant therapies. During follow-up, tumor
recurrence was observed in 73 patients (24%), no recurrence was
observed in 95 patients (31%), and the tumor was present or
progressing in 141 patients (45%). The median follow-up time for all
patients (n = 309) was 27 months (range,
0.3–237 months), and the median follow-up time for patients still
alive (n = 78) was 108 months (range, 21–237
months). Patients who died because of any postoperative complications
were excluded from the survival analyses (n = 9). The clinicopathological characteristics of the patients are
summarized in Table 1
.
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Histochemistry of Hyaluronan.
The biotinylated complex of the hyaluronan-binding region of aggrecan
and link protein (bHABC) was prepared from bovine articular
cartilage and tested for purity, as described previously (25
, 26)
.
The sections were deparaffinized in xylene, rehydrated with graded alcohols, and washed with 0.1 M sodium phosphate buffer [PB (pH 7.4)]. Endogenous peroxidase was inactivated with 1% hydrogen peroxide for 5 min, and nonspecific probe binding was blocked with 1% BSA in PB. The sections were incubated in bHABC (2.5 µg/ml; diluted in 1% BSA) overnight at 4°C. The slides were washed with PB, incubated with avidin-biotin-peroxidase (ABC Vectastain Elite kit; Vector Laboratories, Burlingame, CA), and washed with PB. The color was developed with 0.05% diaminobenzidine tetrahydrochloride (Sigma, St. Louis, MO) and 0.03% hydrogen peroxide in PB. The slides were counterstained with Mayer’s hematoxylin for 2 min, washed, dehydrated, and mounted in Depex (BDH, Poole, United Kingdom). The specificity of the staining was controlled by digesting some of the sections with Streptomyces hyaluronidase in the presence of protease inhibitors before the staining or by blocking the bHABC probe by preincubation with hyaluronan oligosaccharides (27) . The whole staining procedure has been described in detail previously (25) .
CD44 Immunohistochemistry.
Deparaffinized and rehydrated sections were heated in a microwave oven
in 0.01 M citrate buffer (pH 6.0) for 3 x 5
min, incubated in the citrate buffer for 18 min, and washed for
2 x 5 min with PBS. Endogenous peroxidase activity was
blocked by 5% hydrogen peroxide for 5 min, followed by a wash for
2 x 5 min with PBS. The sections were incubated with
1% BSA in PBS for 30 min at 37°C. The primary antibody (mouse
monoclonal antihuman CD44, clone 2C5; R & D Systems, Abingdon, United
Kingdom), which recognizes all forms of CD44 (28)
, was
diluted with 1% BSA to 1:1200 and incubated on the slides overnight at
4°C. The slides were incubated with the secondary antibody for 1 h and washed with PBS for 2 x 5 min. The slides were
then incubated for 1 h in preformed avidin-biotin peroxidase
complex and washed twice for 5 min with PBS, developed with
diaminobenzidine tetrahydrochloride, counterstained with Mayer’s
hematoxylin, dehydrated, cleared, and mounted in Depex.
Evaluation of the Stainings.
All samples were analyzed by two observers (M. A. A., V-M. K.)
unaware of the clinical data. Disagreement in the assessment of
staining was found in less than 10% of the slides examined, and
consensus was reached on further review. The intensity of stromal
hyaluronan was graded into three categories: (a) 1 (weak);
(b) 2 (moderate); and (c) 3 (strong). The
percentage of stroma with the strongest hyaluronan intensity of the
total peri- and intratumoral stromal area was graded into one of three
categories: (a) low (<35%); (b) moderate
(35–75%); or (c) high (>75%), according to the 33rd and
66th percentiles in a frequency distribution. The percentage of
hyaluronan-positive tumor cells of all neoplastic cells in the
section was also estimated, but for statistical analysis, the tumors
were eventually categorized in two groups: (a) hyaluronan
positive; or (b) hyaluronan negative. A tumor was considered
positive if any cancer cell-associated hyaluronan signal was observed.
The intensity of the staining in the tumor epithelium was categorized
into three grades: (a) 0 (no hyaluronan); (b,
hyalurdnan) 1 (weak to moderate hyaluronan); or (c) 2
(strong hyaluronan) using the strongest staining of hyaluronan in the
peri- or intratumoral stroma as an internal positive control. Sections
predigested with Streptomyces hyaluronidase and those
stained with a probe pretreated with hyaluronan oligosaccharides gave
no signal, an indication of the specificity of the method (Fig. 2C)
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Statistical Analysis.
Statistical analyses were performed using the SPSS computer
program package. Spearman correlation coefficients and Wilcoxon tests
were used to evaluate the relationships between continuous variables.
Frequency tables were analyzed using a 
2 test.
Univariate survival analyses were based on the Kaplan-Meier method
(29)
. The differences between curves were analyzed using
the log-rank test. OS was defined as the time interval between the date
of surgery and the date of death due to ovarian cancer. RFS was defined
as the time interval between the date of surgery and the date of
recurrence. Multivariate survival analysis was calculated by means of
Cox’s proportional hazards model in a forward stepwise manner with the
log-likelihood ratio significance test (30)
. The
assumption of proportional hazards was tested by logminlogplots.
Probability values less than 0.05 were regarded as significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. A high level of stromal hyaluronan was more frequent
(59%; 26 of 44) in metastases than in primary tumors (32%;
z = -3.9; P = 0.0001).
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10%. Hyaluronan in cancer cells was located on the plasma membrane
(Fig. 2A)
, but in a few cases (n = 47), it
was also expressed in either the cytoplasm or the nucleus (Fig. 2B)
. Cancer cells expressed hyaluronan in 89% (40 of 45) of
the metastatic lesions available for study. The level of hyaluronan
staining in the primary tumors correlated with that of their metastases
(r = 0.4; P = 0.005).
Correlation of Hyaluronan with CD44 Expression.
We randomly selected 90 primary ovarian tumors and 9 metastases in an
attempt to correlate CD44 positivity with hyaluronan levels.
CD44-positive cancer cells were observed in 70% (63 of 90) of the
primary tumors and in 67% (6 of 9) of their metastases. Stromal
hyaluronan showed a weak inverse correlation (r = -0.2; P = 0.036) with tumor cell
CD44, whereas any kind of cancer cell-associated hyaluronan positivity
did not correlate with CD44 expression at all (r = 0.16; P = 0.13). In the metastatic
lesions, neither stromal nor cancer cell-associated hyaluronan was
related to CD44 positivity.
Hyaluronan and Clinicopathological Characteristics.
A low level of stromal hyaluronan coincided with early FIGO stage
(2 = 7.0; P = 0.008) and mucinous histological type
(2 = 15.3; P = 0.05; Table 2
). A high level of stromal hyaluronan was associated with poor
differentiation (2 = 13.4;
P < 0.0005), serous and clear cell
histological types (2 = 15.3;
P = 0.05), and a large (>2 cm) primary
residual tumor (2 = 5.0;
P = 0.03). Hyaluronan positivity in cancer
cells was associated with poor differentiation of the tumor
(2 = 9.3; P = 0.002). The median age of patients at diagnosis was 62 years and
was not associated with stromal hyaluronan. The follow-up time of
surviving patients did not differ between hyaluronan categories.
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and 4
). Stromal hyaluronan was also a significant prognostic factor as a
continuous variable in both OS (P = 0.002)
and RFS (P = 0.003). Other factors in
univariate analysis significantly indicating a short OS were poor
differentiation (P < 0.00005), advanced FIGO
stage (P < 0.00005), primary residual
tumor > 2 cm (P < 0.00005),
and older than median age at diagnosis (P = 0.04). In addition, stromal hyaluronan significantly predicted OS when
stratified by early (P = 0.006) or advanced
FIGO stage (P = 0.01) and by grade 1–2
(P = 0.02) or grade 3 (P = 0.04). Short RFS was significantly predicted by the serous
histological type (P = 0.025), poor
differentiation (P = 0.047), advanced FIGO
stage (P = 0.0001), and primary residual
tumor > 2 cm (P < 0.00005).
The percentage of hyaluronan-positive cancer cells, the intensity of
the cell-associated hyaluronan signal, and the localization of the
signal in the cytoplasm or nucleus had no prognostic significance in
univariate analyses.
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. Because there was no statistical difference between low and moderate
levels of stromal hyaluronan in univariate analyses, these two groups
were combined. Stromal hyaluronan expression was an independent
prognostic factor in both OS (P = 0.0003) and
RFS (P = 0.003). The other independent
prognostic factors were primary residual tumor, FIGO stage,
histological grade, and adjuvant chemotherapy (for OS) and primary
residual tumor and histological type (for RFS). When Cox’s analyses
were restricted to patient subgroups with FIGO stage I-II
(n = 126) or stage III-IV
(n = 143) disease, a high level of stromal
hyaluronan retained its independent prognostic value for poor OS with a
RR of 1.89 (95% CI, 1.03–3.45; P = 0.039)
in stage I-II and a RR of 1.71 (95% CI, 1.15–2.54;
P = 0.008) in stage III-IV. The high level of
stromal hyaluronan accumulation predicted recurrence with a RR of 2.15
(95% CI, 1.09–4.25; P = 0.028) in stage
I-II (n = 106) and a RR of 4.35 (95% CI,
1.89–10.03; P = 0.0006) in stage III-IV
(n = 47).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Structural cues in the surrounding matrix, particularly the integrin-binding proteins presented by the basal lamina, are known to control gene expression and determine the differentiation of mammary epithelial cells. This control is so strong that unless normal matrix structure is altered, malignancy will not progress, even in the presence of multiple chromosomal mutations in the epithelial cells (32) . The present findings suggest that an abnormally high level of hyaluronan is one of the matrix changes creating tumor-permissive conditions. Similar results were obtained in breast (33) and colon cancer (34) , an indication of a more universal influence of hyaluronan in malignancies originating in monolayered epithelial.
The most probable source of increased stromal hyaluronan is its synthesis by the local mesenchymal cells (35, 36, 37) . Mouse ovarian cancer cells stimulate hyaluronan production on mouse mesenteric surfaces and in tumor cell clumps (38) . Although the molecular basis of such a stimulation is not understood, various growth factors or direct cellular contacts are probably involved (37 , 39 , 40) . In metastatic foci, the levels of stromal hyaluronan were higher than those in the corresponding primary tumors, suggesting that those cancer cells capable of a strong induction of stromal hyaluronan have acquired a growth advantage after shedding from the primary tumor. We therefore propose that hyaluronan synthesis is important (perhaps vital) for tumor progression. This suggestion is in line with recent experimental studies indicating that overexpression of a hyaluronan synthase gene transfected into cancer cells enhances their anchorage-independent growth, tumorigenicity, and metastatic potential (41 , 42) .
Our data indicate that the ability of ovarian cancer cells to induce peri- and intratumoral hyaluronan accumulation was not dependent on the expression of CD44 on tumor cell surface. This is interesting because 40–50% of human ovarian tumor cell attachment to mouse peritoneum is based on cell surface CD44 interacting with hyaluronan on mesothelial cells (16) . In the mouse model, an anti-CD44 antibody reduces the number of peritoneal tumor deposits (20 , 38) , suggesting that CD44 is important in the adhesion and metastatic growth of ovarian cancer. It seems that the CD44-dependent adherence of cancer cells onto mesothelial surface hyaluronan is a phenomenon unrelated to the stromal hyaluronan reaction and may represent a different stage in the progression of ovarian cancer.
The current study confirmed the importance of the standard prognostic factors (31) , e.g., the FIGO stage and residual tumor size, and indicated that the level of stromal hyaluronan offers an additional means to refine disease prognostication. Novel molecular markers with a biological rationale such as the hyaluronan reaction can be used to tailor the therapy in a wide clinical spectrum of epithelial ovarian cancers. The clinical relevance of this concept is supported by the fact that the high level of stromal hyaluronan retained its predictive value for poor prognosis within patient subgroups such as FIGO stage I-II and III-IV, independently of surgery and adjuvant chemotherapy.
The resistance of ovarian cancer cells to chemotherapeutic agents due to intrinsic factors, insufficient drug penetration, or reduced growth fraction (43 , 44) is one of the most important limitations in the treatment of this group of malignancies. The induction of stromal hyaluronan synthesis might be a part of the mechanism whereby chemotherapeutic resistance develops. Hyaluronidase is a relatively nontoxic enzyme, which enhances drug penetration by degrading the gel-like hyaluronan coat shielding the cancer cells, and has been successfully used as a chemosensitizer in bladder cancer (45) , squamous carcinomas of the neck (46) , breast cancer (44 , 47) and cutaneous melanoma (48) . The present data indicate that the most aggressive ovarian cancers show the highest hyaluronan levels; therefore, hyaluronidase could be particularly useful in increasing drug penetration in these cancers. Inhibition of hyaluronan synthesis could be another treatment option, but there are currently no specific methods available for inhibition of hyaluronan synthesis. In the future, understanding the regulation of the recently cloned hyaluronan synthase genes (49) may provide opportunities for the inhibition of hyaluronan synthesis. Meanwhile, the value of hyaluronan concentration assays in serum and ascites should also be evaluated in the follow-up surveillance of ovarian cancer patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Finnish Cancer Foundation, The
Finnish Medical Society Duodecim, The North Savo Cancer Fund and EVO
funds of Kuopio University Hospital. 
2 To whom requests for reprints should be
addressed, at Department of Pathology and Forensic Medicine, University
of Kuopio, P. O. Box 1627, FIN-70211 Kuopio, Finland. Phone:
358-17-173311; Fax: 358-17-162753.
3 The abbreviations used are: FIGO, International
Federation of Gynecology and Obstetrics; OS, overall survival; RFS,
recurrence-free survival; RR, relative risk; CI, confidence interval;
bHABC, biotinylated hyaluronan binding region and the link protein
complex.
Received 6/18/99. Accepted 11/ 1/99.
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M. A. Simpson, J. Reiland, S. R. Burger, L. T. Furcht, A. P. Spicer, T. R. Oegema Jr., and J. B. McCarthy Hyaluronan Synthase Elevation in Metastatic Prostate Carcinoma Cells Correlates with Hyaluronan Surface Retention, a Prerequisite for Rapid Adhesion to Bone Marrow Endothelial Cells J. Biol. Chem., May 18, 2001; 276(21): 17949 - 17957. [Abstract] [Full Text] [PDF]
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