title: Prognostic significance of highly sulfated chondroitin sulfates in ovarian cancer defined by the single chain antibody GD3A11.
abstract: OBJECTIVE
  The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Chondroitin sulfate (CS), a class of sulfated polysaccharides, is abundantly present in the ECM of ovarian cancer. Structural alterations of CS chains (i.e. sulfation pattern) have been demonstrated to play a role in cancer development and progression. In this study we investigate the potential of highly sulfated CS as a biomarker in ovarian cancer using the single chain antibody GD3A11 selected by the phage display technology.
  
  
  METHODS
  The specificity of the antibody was determined by an indirect ELISA. GD3A11 epitope expression was assessed by immunohistochemistry in healthy organs, benign and malignant ovarian tumors (N=359) and correlated to clinical parameters. The CHST15 gene, responsible for the biosynthesis of highly sulfated CS was evaluated for mutation and methylation status.
  
  
  RESULTS
  The GD3A11 epitope was minimally expressed in normal organs. Intense expression was observed in the ECM of different ovarian cancer subtypes, in contrast to benign ovarian tumors. Expression was independent of tumor grade, FIGO stage, and the use chemotherapy. For the aggressive ovarian cancer phenotype, intense expression was identified as an independent predictor for poor prognosis. CHST15 gene analysis showed no mutations nor an altered methylation status.
  
  
  CONCLUSIONS
  Specific highly sulfated CS motifs expressed in the tumoral ECM hold biomarker potential in ovarian cancer patients. These matrix motifs constitute a novel class of biomarkers with prognostic significance and may be instrumental for innovative diagnostic and therapeutic applications (e.g. targeted therapy) in management of ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Biochemistry, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Sophieke.vandersteen@radboudumc.nl.
authors.forename: Sophieke C H A
authors.initials: SC
authors.lastname: van der Steen
authors.affiliation: Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Angela A G
authors.initials: AA
authors.lastname: van Tilborg
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Biochemistry, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Myrtille J E
authors.initials: MJ
authors.lastname: Vallen
authors.affiliation: Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Bulten
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002809:Chondroitin Sulfates / Q000276:immunology* / Q000378:metabolism*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000276:immunology; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010053:Ovary / Q000378:metabolism; D010641:Phenotype; D057127:Single-Chain Antibodies / Q000276:immunology / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C411874:CHST15 protein, human; D000939:Epitopes; D008562:Membrane Glycoproteins; D057127:Single-Chain Antibodies; D002809:Chondroitin Sulfates; D015238:Sulfotransferases
keywords: Biomarker; Chondroitin sulfate; Glycosaminoglycans; Ovarian cancer; Single chain variable fragment antibody