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Distribution and Clinical Significance of Heparan Sulfate Proteoglycans in Ovarian Cancer

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Distribution and Clinical Significance of Heparan Sulfate Proteoglycans in Ovarian Cancer 5178 Vol. 10, 5178–5186, August 1, 2004 Clinical Cancer Research Distribution and Clinical Significance of Heparan Sulfate Proteoglycans in Ovarian Cancer E. June Davies,1 Fiona H. Blackhall,1 decan-1 and glypican-1 were poor prognostic factors for Jonathan H. Shanks,2 Guido David,3 survival in univariate analysis. Alan T. McGown,4 Ric Swindell,5 Conclusion: We report for the first time distinct pat- 6 7 terns of expression of cell surface and extracellular matrix Richard J. Slade, Pierre Martin-Hirsch, heparan sulfate proteoglycans in normal ovary compared 1 1 John T. Gallagher, and Gordon C. Jayson with ovarian tumors. These data reinforce the role of the 1Cancer Research UK and University of Manchester Department of tumor stroma in ovarian adenocarcinoma and suggest that Medical Oncology, Paterson Institute for Cancer Research, stromal induction of syndecan-1 contributes to the patho- Manchester, England; 2Department of Histopathology, Christie Hospital NHS Trust, Manchester, England; 3Department of Medicine, genesis of this malignancy. University of Leuven, Leuven, Belgium.; 4Cancer Research UK Department of Experimental Pharmacology, Paterson Institute for Cancer Research, Manchester, England; 5Department of Medical INTRODUCTION Statistics, Christie Hospital NHS Trust, Manchester, England; The heparan sulfate proteoglycans (HSPGs) play diverse 6Department of Obstetrics and Gynaecology, Hope Hospital, Salford, Manchester, England; 7Department of Gynaecological Oncology, St. roles in tumor biology by mediating adhesion and migration and Mary’s Hospital, Oxford Road, Manchester, England cellular responses to mitogenic and angiogenic growth factors (1). They have been proposed as critical regulators of tumor invasion and metastasis (2). The major HSPG families at the cell ABSTRACT surface are the four transmembrane syndecans (syndecan-1 Purpose: Heparan sulfate proteoglycans have been im- through -4) and the 5 glypican family members (glypican-1 plicated in cancer cell growth, invasion, metastasis, and through -5) that are linked to the cell membrane via a phos- angiogenesis. This study was designed to compare their phatidyl-inositol anchor (1). Perlecan is a large modular protein expression in normal ovary and ovarian tumors and then to that is abundant in the extracellular matrix and basement mem- examine their prognostic significance in ovarian cancer. branes of normal tissues and blood vessels (3, 4). Experimental Design: The expression of syndecan-1, -2, These distinctly different proteins are designated HSPGs -3, and -4, glypican-1, and perlecan was assessed by immu- because they are modified after translation by the covalent nohistochemistry in 147 biopsies that included normal ovary attachment of two or more chains of the linear polysaccharide and benign, borderline, and malignant ovarian tumors. heparan sulfate. The heparan sulfate chains are responsible for Clinical data, including tumor stage, performance status, much of the biological role of the HSPGs because they encode treatment, and survival, were collected. Univariate and mul- the recognition sites for numerous heparin-binding proteins, tivariate analyses were performed to evaluate prognostic such as acidic and basic fibroblast growth factor (bFGF; Ref. 5), significance. vascular endothelial growth factor (6), and hepatocyte growth Results: The expression patterns of syndecan-1 and per- factor/scatter factor (7, 8), which have well-documented roles in lecan were altered in ovarian tumors compared with normal tumor biology. These ligands use HSPGs as co-receptors to ovary. Syndecan-1 was not detected in normal ovary but was mediate their binding to specific tyrosine kinase receptors and present in the epithelial and stromal cells of benign and promote signal transduction (9). HSPGs also participate in cell- borderline tumors and in ovarian adenocarcinomas. Perle- cell and cell-matrix adhesion complexes by binding to structural can expression was decreased in basement membranes that proteins of the extracellular matrix, including collagens, lami- were disrupted by cancer cells but maintained in the base- nin, and fibronectin. Notably, syndecan-4 cooperates with inte- ment membranes of blood vessels. Syndecan-2, -3, and -4, grins and regulates the distribution and activity of protein kinase and glypican-1 were expressed in normal ovary and benign C in focal adhesions (10). Phosphorylation of the cytoplasmic and malignant ovarian tumors. Stromal expression of syn- domain of syndecan-2 has also been noted to occur independ- ently of integrin signaling and plays a role in the assembly of fibronectin and laminin (11). Syndecans, glypicans, and perlecan are expressed in cell-, tissue- and development-specific patterns (2). Several studies Received 8/27/03; revised 3/29/04; accepted 5/19/04. have demonstrated altered expression of HSPGs in cancer (1), The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked but with respect to ovarian cancer the only HSPG that has been advertisement in accordance with 18 U.S.C. Section 1734 solely to studied in detail is the phosphatidyl-inositol-linked HSPG, indicate this fact. glypican-3. Various mutations in the glypican-3 gene cause Requests for reprints: Gordon Jayson, Cancer Research United King- Simpson–Golabi–Behmel syndrome, which is associated with dom, Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. an increased risk of Wilm’s tumor and neuroblastoma (12, 13). Phone: 44 161 446 3606; Fax: 44 161 446 3461; E-mail: Gordon. Mutations of glypican-3 and loss of expression due to hyper- [email protected]. methylation have been demonstrated in a significant proportion Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 5179 of sporadic ovarian cancers, suggesting that glypican-3 may act Microscope slides, precoated with 2% 3-aminopropyl- as a tumor suppressor in this and other malignancies (14–17). triethoxysilate–acetone for 5 min, were prepared. Embedded However, in a study of ovarian cancer cell lines, transmembrane tissue samples were cut in 7-␮m sections, air-dried, and stored HSPGs, in addition to phosphatidylinositol-linked families, me- at Ϫ20°C. The slides were placed in a staining rack at room diated adhesion to collagen I and III and fibronectin, suggesting temperature, immersed in 100% acetone for 10 min, air dried for that other HSPGs in addition to glypican-3 play a role in vivo 1 min, and then immersed in PBS. Formalin-fixed, paraffin- (18). We therefore performed this study to define the expression embedded ovarian tissues were cut at a thickness of 3 ␮mon patterns of syndecan-1, -2, -3 and -4; glypican-1; and perlecan in 3-aminopropyl-triethoxysilate-coated slides, dewaxed by im- normal ovary and benign, borderline, and malignant ovarian mersion in xylene for 10 min, rehydrated in a graded series of tumors. We then compared the prognostic importance of HSPG ethanol baths, and finally transferred to a PBS bath for immu- expression with that of standard prognostic factors in ovarian nostaining. One of the serial sections was stained with hema- adenocarcinoma. toxylin and eosin Conventional immunohistochemical techniques were used. Briefly, after endogenous peroxidase was blocked with 0.3% MATERIALS AND METHODS hydrogen peroxide in PBS–methanol, the slide was placed in a Patients and Samples. Samples of frozen ovarian tissue bath of PBS containing 0.05% Tween 20 for 5 min. The sections were taken from archived cases held in the tumor bank at the were then blocked with 20% normal rabbit serum in PBS and Christie Hospital and Paterson Institute for Cancer Research, incubated with primary monoclonal antibodies, at the concen- Manchester. These had been obtained during surgery, cut into trations shown above, in 10% normal rabbit serum overnight at 5-mm-diameter cubes, frozen by immersion in liquid nitrogen 4°C. After washing, horseradish peroxidase-conjugated rabbit within1hofresection, and stored at Ϫ80°C. In addition, antimouse secondary antibody (diluted 1:200 in 10% normal formalin-fixed, paraffin-embedded samples were obtained from rabbit serum) was added for 30 min at room temperature. The histopathology departments where the original surgery had sections were then placed in 0.05% diaminobenzidine solution taken place for patients who were referred to our center after (DAKO, Ely, United Kingdom) for 5 min. After incubation with initial surgery for chemotherapy. Formalin-fixed, paraffin- diaminobenzidine the slides were washed, counterstained in embedded samples of age-matched normal ovary were obtained hematoxylin for 1 min, and washed in running water at 37°C for from archive material held in the Histopathology Department of 1 min. They were then placed in alkaline water, dehydrated, the Christie Hospital NHS Trust. The South and Central cleared, and mounted. The final dilution of each antibody was Manchester Ethical Committees approved this study. determined after preliminary serial dilution studies. These were All histological samples were reviewed by a histopatholo- chosen to yield an intermediate level of positive staining in gist who specializes in gynecological oncology (J. H. S.). Sam- control tissues. Deglycanation to remove heparan sulfate chains ples that were included in the study had a diagnosis of normal was investigated but did not
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