Sucrose octasulfate regulates fibroblast growth factor-2 binding, transport, and activity: potential for regulation of tumor growth.
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.
Fannon
Michael
M
Department of Ophthalmology and Visual Science, University of Kentucky, Lexington, Kentucky, USA. michael.fannon@uky.edu
Forsten-Williams
Kimberly
K
Nugent
Matthew A
MA
Gregory
Kalvin J
KJ
Chu
Chia Lin
CL
Goerges-Wildt
Adrienne L
AL
Panigrahy
Dipak
D
Kaipainen
Arja
A
Barnes
Carmen
C
Lapp
Cathy
C
Shing
Yuen
Y
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
D016222:Fibroblast Growth Factor 2; D013395:Sucrose; C053081:sucrose octasulfate