TY - JOUR
T1 - FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells
AU - Reiland, Jane
AU - Kempf, Doty
AU - Roy, Madhuchhanda
AU - Denkins, Yvonne
AU - Marchetti, Dario
N1 - Funding Information:
Abbreviations: DME/F-12, Dulbecco’s modified Eagle’s F-12 medium; ECM, extracellular matrix; ERK, extracellular signal–regulated kinase; FAK, focal adhesion kinase; FGF2, fibroblast growth factor-2; FGFR, FGF receptors; Hep I, heparitinase I; Hep III, heparitinase III; HPSE, heparanase; HS, heparan sulfate glycosaminoglycan chains; HSPG, heparan sulfate proteoglycans Address all correspondence to: Dr. Dario Marchetti, Department of Comparative Biomedical Sciences-SVM, Louisiana State University-Baton Rouge, Room 2522, Skip Bertman Drive, Baton Rouge, LA 70803. E-mail: [email protected] 1This work was supported by a grant from the Governor’s Biotechnology Initiative of the State of Louisiana and by grants from the National Institutes of Health (5R0-1CA86832 and 1R21 CA 103955, to D.M.), Phillip Morris USA, and Phillip Morris International (to D.M). Received 20 March 2006; Revised 15 May 2006; Accepted 17 May 2006.
PY - 2006
Y1 - 2006
N2 - Heparanase (HPSE) and fibroblast growth factor-2 (FGF2) are critical regulators of melanoma angiogenesis and metastasis. Elevated HPSE expression contributes to melanoma progression; however, further augmentation of HPSE presence can inhibit tumorigenicity. HPSE enzymatically cleaves heparan sulfate glycosaminoglycan chains (HS) from proteoglycans. HS act as both low-affinity FGF2 receptors and coreceptors in the formation of high-affinity FGF2 receptors. We have investigated HPSE's ability to modulate FGF2 activity through HS remodeling. Extensive HPSE degradation of human metastatic melanoma cells (70W) inhibited FGF2 binding. Unexpectedly, treatment of 70W cells with low HPSE concentrations enhanced FGF2 binding. In addition, HPSE-unexposed cells did not phosphorylate extracellular signal-related kinase (ERK) or focal adhesion kinase (FAK) in response to FGF2. Conversely, in cells treated with HPSE, FGF2 stimulated ERK and FAK phosphorylation. Secondly, the presence of soluble HPSE-degraded HS enhanced FGF2 binding and ERK phosphorylation at low HS concentrations. Higher concentrations of soluble HS inhibited FGF2 binding, but FGF2 signaling through ERK remained enhanced. Soluble HS were unable to support FGF2-stimulated FAK phosphorylation irrespective of HPSE treatment. Finally, cell exposure to HPSE or to HPSE-degraded HS modulated FGF2-induced angiogenesis in melanoma. In conclusion, these effects suggest relevant mechanisms for the HPSE modulation of melanoma growth factor responsiveness and tumorigenicity.
AB - Heparanase (HPSE) and fibroblast growth factor-2 (FGF2) are critical regulators of melanoma angiogenesis and metastasis. Elevated HPSE expression contributes to melanoma progression; however, further augmentation of HPSE presence can inhibit tumorigenicity. HPSE enzymatically cleaves heparan sulfate glycosaminoglycan chains (HS) from proteoglycans. HS act as both low-affinity FGF2 receptors and coreceptors in the formation of high-affinity FGF2 receptors. We have investigated HPSE's ability to modulate FGF2 activity through HS remodeling. Extensive HPSE degradation of human metastatic melanoma cells (70W) inhibited FGF2 binding. Unexpectedly, treatment of 70W cells with low HPSE concentrations enhanced FGF2 binding. In addition, HPSE-unexposed cells did not phosphorylate extracellular signal-related kinase (ERK) or focal adhesion kinase (FAK) in response to FGF2. Conversely, in cells treated with HPSE, FGF2 stimulated ERK and FAK phosphorylation. Secondly, the presence of soluble HPSE-degraded HS enhanced FGF2 binding and ERK phosphorylation at low HS concentrations. Higher concentrations of soluble HS inhibited FGF2 binding, but FGF2 signaling through ERK remained enhanced. Soluble HS were unable to support FGF2-stimulated FAK phosphorylation irrespective of HPSE treatment. Finally, cell exposure to HPSE or to HPSE-degraded HS modulated FGF2-induced angiogenesis in melanoma. In conclusion, these effects suggest relevant mechanisms for the HPSE modulation of melanoma growth factor responsiveness and tumorigenicity.
KW - Angiogenesis
KW - FGF2 binding
KW - Heparan sulfate
KW - Heparanase
KW - Malignant melanoma
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U2 - 10.1593/neo.06244
DO - 10.1593/neo.06244
M3 - Article
C2 - 16867222
AN - SCOPUS:33745949315
SN - 1522-8002
VL - 8
SP - 596
EP - 606
JO - Neoplasia
JF - Neoplasia
IS - 7
ER -