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Primary ovarian carcinomas and abdominal metastasis contain 4,6-disulfated chondroitin sulfate rich regions, which provide adhesive properties to tumour cells.

Vallen MJ, Schmidt S, Oosterhof A, Bulten J, Massuger LF, van Kuppevelt TH - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Strong staining for CSE in tumours.Sections of paraffin embedded primary serous ovarian carcinoma were stained for CS, DS and CSE using antibodies IO3H10, GD3A12 and GD3G7, respectively. A) Haematoxylin-Eosin staining showing tumourous versus non-tumourous regions. Non-tumourous regions are indicated with an asterix (*). B–E) Overall staining for CS (B: antibody IO3H10), DS (C:antibody GD3A12) and CSE (D, E antibody GD3G7). Note overall staining for CS and DS, but strong CSE staining in intratumoural stroma, including small tumour capillaries (E, arrows). Also note mild staining of large blood vessels in non-tumourous areas (E) Staining for CSE indicated a gradient of CSE at the boundary of tumour and non-tumourous tissue (**). Bar: 100 µm.
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pone-0111806-g001: Strong staining for CSE in tumours.Sections of paraffin embedded primary serous ovarian carcinoma were stained for CS, DS and CSE using antibodies IO3H10, GD3A12 and GD3G7, respectively. A) Haematoxylin-Eosin staining showing tumourous versus non-tumourous regions. Non-tumourous regions are indicated with an asterix (*). B–E) Overall staining for CS (B: antibody IO3H10), DS (C:antibody GD3A12) and CSE (D, E antibody GD3G7). Note overall staining for CS and DS, but strong CSE staining in intratumoural stroma, including small tumour capillaries (E, arrows). Also note mild staining of large blood vessels in non-tumourous areas (E) Staining for CSE indicated a gradient of CSE at the boundary of tumour and non-tumourous tissue (**). Bar: 100 µm.

Mentions: CS and DS are present throughout both the tumoural and non-tumoural stroma. This was demonstrated using antibodies IO3H10 (overall CS staining) and GD3A12 (overall DS staining) (fig. 1B and C) [11], [30]. We also applied antibody GD3G7 which defines a specific epitope harboring contiguous 4,6 disulfated (CSE) disaccharide units, a rare CS modification. 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 (pathological) blood vessels. A CSE gradient was seen at places where tumour tissue is adjacent to non-tumourous tissue (fig. 1D and E).


Primary ovarian carcinomas and abdominal metastasis contain 4,6-disulfated chondroitin sulfate rich regions, which provide adhesive properties to tumour cells.

Vallen MJ, Schmidt S, Oosterhof A, Bulten J, Massuger LF, van Kuppevelt TH - PLoS ONE (2014)

Strong staining for CSE in tumours.Sections of paraffin embedded primary serous ovarian carcinoma were stained for CS, DS and CSE using antibodies IO3H10, GD3A12 and GD3G7, respectively. A) Haematoxylin-Eosin staining showing tumourous versus non-tumourous regions. Non-tumourous regions are indicated with an asterix (*). B–E) Overall staining for CS (B: antibody IO3H10), DS (C:antibody GD3A12) and CSE (D, E antibody GD3G7). Note overall staining for CS and DS, but strong CSE staining in intratumoural stroma, including small tumour capillaries (E, arrows). Also note mild staining of large blood vessels in non-tumourous areas (E) Staining for CSE indicated a gradient of CSE at the boundary of tumour and non-tumourous tissue (**). Bar: 100 µm.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4221137&req=5

pone-0111806-g001: Strong staining for CSE in tumours.Sections of paraffin embedded primary serous ovarian carcinoma were stained for CS, DS and CSE using antibodies IO3H10, GD3A12 and GD3G7, respectively. A) Haematoxylin-Eosin staining showing tumourous versus non-tumourous regions. Non-tumourous regions are indicated with an asterix (*). B–E) Overall staining for CS (B: antibody IO3H10), DS (C:antibody GD3A12) and CSE (D, E antibody GD3G7). Note overall staining for CS and DS, but strong CSE staining in intratumoural stroma, including small tumour capillaries (E, arrows). Also note mild staining of large blood vessels in non-tumourous areas (E) Staining for CSE indicated a gradient of CSE at the boundary of tumour and non-tumourous tissue (**). Bar: 100 µm.
Mentions: CS and DS are present throughout both the tumoural and non-tumoural stroma. This was demonstrated using antibodies IO3H10 (overall CS staining) and GD3A12 (overall DS staining) (fig. 1B and C) [11], [30]. We also applied antibody GD3G7 which defines a specific epitope harboring contiguous 4,6 disulfated (CSE) disaccharide units, a rare CS modification. 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 (pathological) blood vessels. A CSE gradient was seen at places where tumour tissue is adjacent to non-tumourous tissue (fig. 1D and E).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus