title: Sucrose octasulfate regulates fibroblast growth factor-2 binding, transport, and activity: potential for regulation of tumor growth.
abstract: The antithrombotic activity of heparin has largely been credited with the success found in some cancer treatment by heparin. There are, however, many potent growth factors involved in tumor and blood vessel growth that bind to heparin with high affinity and their regulation by heparin may play a role in heparin's efficacy. We therefore chose to study the activity of a heparin analog, sucrose octasulfate (SOS), which has been similarly shown to interact with heparin-binding growth factors. Using mouse melanoma and lung carcinoma models, we demonstrate in vivo inhibition of tumor growth by SOS. SOS, however, showed little effect in coagulation assays indicating that this activity was not a primary mechanism of action for this molecule. Studies were then performed to assess the effect of SOS on basic fibroblast growth factor (FGF-2) activity, a growth factor which promotes tumor and blood vessel growth and is produced by B16 melanoma cells. SOS potently inhibited FGF-2 binding to endothelial cells and stripped pre-bound FGF-2 from cells. SOS also regulated FGF-2 stimulated proliferation. Further, SOS facilitated FGF-2 diffusion through Descemet's membrane, a heparan sulfate-rich basement membrane from the cornea, suggesting a possible role in FGF-2 clearance. Our results suggest that molecules such as SOS have the potential to remove growth factors from tumor microenvironments and the approach offers an attractive area for further study.
authors.affiliation: Department of Ophthalmology and Visual Science, University of Kentucky, Lexington, Kentucky, USA. michael.fannon@uky.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Fannon
authors.forename: Kimberly
authors.initials: K
authors.lastname: Forsten-Williams
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nugent
authors.forename: Kalvin J
authors.initials: KJ
authors.lastname: Gregory
authors.forename: Chia Lin
authors.initials: CL
authors.lastname: Chu
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Goerges-Wildt
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.forename: Arja
authors.initials: A
authors.lastname: Kaipainen
authors.forename: Carmen
authors.initials: C
authors.lastname: Barnes
authors.forename: Cathy
authors.initials: C
authors.lastname: Lapp
authors.forename: Yuen
authors.initials: Y
authors.lastname: Shing
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D002196:Capillaries / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003886:Descemet Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013395:Sucrose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016222:Fibroblast Growth Factor 2; D013395:Sucrose; C053081:sucrose octasulfate