Heparan sulphate synthetic and editing enzymes in ovarian cancer - PubMed (original) (raw)

Comparative Study

. 2007 May 21;96(10):1544-8.

doi: 10.1038/sj.bjc.6603747. Epub 2007 Apr 17.

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Comparative Study

Heparan sulphate synthetic and editing enzymes in ovarian cancer

A C Backen et al. Br J Cancer. 2007.

Abstract

Several angiogenic growth factors including fibroblast growth factors 1 and 2 (FGF1 and FGF2) depend on heparan sulphate (HS) for biological activity. We previously showed that all cellular elements in ovarian tumour tissue synthesised HS but biologically active HS (i.e. HS capable of binding FGF2 and its receptor) was confined to ovarian tumour endothelium. In this study, we have sought to explain this observation. Heparan sulphate sulphotransferases 1 and 2 (HS6ST1 and HS6ST2) attach sulphate groups to C-6 of glucosamine residues in HS that are critical for FGF2 activation. These enzymes were strongly expressed by tumour cells, but only HS6ST1 was found in endothelial cells. Immunostaining with the 3G10 antibody of tissue sections pretreated with heparinases indicated that HS proteoglycans were produced by tumour and endothelial cells. These results indicated that, in contrast to the endothelium, HS produced by tumour cells may be modified by cell-surface heparanase (HPA1) or endosulphatase (SULF). Protein and RNA analysis revealed that HPA1 was strongly expressed by ovarian tumour cells in eight of ten specimens examined. HSULF-1, which removes specific 6-O-sulphate groups from HS, was abundant in tumour cells but weakly expressed in the endothelium. If this enzyme was responsible for the lack of biologically active HS on the tumour cell surface, we would expect exogenous FGF2 binding to be preserved; we showed previously that this was indeed the case although FGF2 binding was reduced compared to the endothelium and stroma. Thus, the combined effects of heparanase and HSULF could account for the lack of biologically active HS in tumour cells rather than deficiencies in the biosynthetic enzymes.

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Figures

Figure 1

Figure 1

(A) HS6ST1 ISH shows RNA to be present in ovary tumour and endothelial cells, but absent in stroma and normal ovary (inset). (B) HS6ST2 ISH shows RNA to be present in ovary tumour cells, but absent in endothelial cells, stroma and normal ovary (inset). (C) 10E4, an anti-HS monoclonal antibody was used to demonstrate that intact HS chains were only present on endothelial cells in ovarian tumours. (D) 3G10 antibody was used to detect the HS stubs that remain after heparinase digestion. A negative control shows 3G10 staining to be negative without prior heparinase digestion (inset). (E) Heparanase ISH shows RNA to be present in ovary tumour cells, but absent in endothelial cells and stroma. (F) Heparanase IHC shows protein to be present in ovary tumour cells, but absent in endothelial cells and stroma. (G) Heparanase IHC on normal human ovary shows protein to be present at a low level in most cells. (H) HSULF-1 ISH shows RNA to be present in ovary tumour cells, but absent in endothelial cells, stroma and normal ovary (inset). Each scale bar represents 400 _μ_m.

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