Primary ovarian carcinomas and abdominal metastasis contain 4,6-disulfated chondroitin sulfate rich regions, which provide adhesive properties to tumour cells.
High mortality in ovarian cancer patients is primarily caused through rapid metastasis of the tumour, but the underlying mechanisms are poorly understood. Glycosaminoglycans, are abundantly present in tumours and chondroitin sulfate-E (CSE), a highly 4,6-sulfated glycosaminoglycan, has been indicated to play a role in carcinogenesis. In this study we investigated the presence of CSE in ovarian cancer metastasis and studied its role in tumour cell adhesiveness and migration. CSE was studied immunohistochemically in primary ovarian carcinomas and abdominal metastases using the single chain antibody GD3G7. The role of CSE was studied in 2D (scratch assays) and 3D (collagen matrices, spheroids) systems using SKOV3 cells applying 1: overexpression of CSE by stable transfection with DNA encoding GalNAc4S-6 sulfotransferase, 2: enzymatic removal of CS, and 3: addition of CSE. In ovarian cancer tissue, CSE expression was predominantly seen in the stromal compartment of both primary ovarian carcinomas and metastases, with a comparable degree of intensity and extent. Overexpression of CSE disaccharide units by tumour cells increased their adhesive properties which was especially seen in tumour spheroid formation. Increased expression of CSE reduced cell migration. Addition of free CSE had similar effects. The data presented here indicate that CSE is associated with metastatic lesions and that it provides tumours with adhesive properties. CSE rich motifs are put forward as a potential target for ovarian cancer therapy.
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
Myrtille J E
MJ
Vallen
Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Samuel
S
Schmidt
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Arie
A
Oosterhof
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
Johan
J
Bulten
Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
Leon F A G
LF
Massuger
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Toin H
TH
van Kuppevelt
D000005:Abdomen / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002809:Chondroitin Sulfates / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
C096808:chondroitin 4,6-disulfate; D002809:Chondroitin Sulfates; C416670:N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase; D015238:Sulfotransferases