Heparan sulphate synthetic and editing enzymes in ovarian cancer.
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.
Backen
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AC
Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital, Cancer Research UK and University of Manchester, Manchester M20 4BX, UK. Alison.Backen@Manchester.ac.uk
Cole
C L
CL
Lau
S C
SC
Clamp
A R
AR
McVey
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R
Gallagher
J T
JT
Jayson
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GC
D002277:Carcinoma / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D000099175:Heparanase
D005966:Glucuronidase; D006497:Heparan Sulfate; D012333:RNA, Messenger; D015238:Sulfotransferases; D000099175:Heparanase; C485757:HS6ST2 protein, human; C470791:SULF1 protein, human; C404189:heparan sulfate 6-O-sulfotransferase