Abstract
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.
Highlights
Ovarian cancer is the fifth leading cause of cancer death in women worldwide
Using an antibody recognizing a motif that is rich in chondroitin sulfate-E (CSE) units (GD3G7), we recently showed strong upregulation of CSE in primary ovarian carcinomas which correlated with poor prognostic parameters such as high grade, and advanced FIGO stage [19]
In accordance with our previous studies [19,31], GD3G7 expression in ovarian carcinomas was predominantly seen in the intratumoural stroma, the basement membrane zone underlying tumour cells, and the region surrounding blood vessels
Summary
Ovarian cancer is the fifth leading cause of cancer death in women worldwide. Each year this disease accounts for approximately 225,000 new patients and 140,000 deaths [1]. Despite advances in cytoreductive surgery and modern chemotherapy, five-year survival rates are not improving. This high lethality is primarily due to the fact that patients are diagnosed with advanced stage disease (FIGO III–IV), when the tumour is already widely spread [2,3]. Haematogenous dissemination of ovarian cancer cells is rare. Ovarian carcinomas mainly disseminate via the transcoelomic route. Tumour cells and cell aggregates (spheroids) are shed from the primary tumour into the peritoneal space, where they preferably seed and attach to the peritoneum and omentum [4,5]
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