An FGF-binding protein (FGF-BP) exerts its biological function by parallel paracrine stimulation of tumor cell and endothelial cell proliferation through FGF-2 release.
Fibroblast growth factors FGF-1 (aFGF) and FGF-2 (bFGF) are found in most embryonic and adult normal and tumor tissues, where they are immobilized in the extracellular matrix (ECM). Mobilization of these FGFs is part of a tightly controlled process resulting in the activation of high-affinity FGF receptors. Recently, we have shown that a secreted FGF-binding protein (FGF-BP) binds non-covalently to FGF-2 and is able to release it from the ECM. This process of growth factor bioactivation seems to play a pivotal role in the growth of squamous cell carcinomas, especially through induction of tumor angiogenesis. Since previous studies provided only indirect evidence for the proposed mechanism of FGF-BP-mediated FGF-2 release, we decided to use recombinant purified FGF-BP to study further the underlying mechanism of FGF-BP action. Here we show that FGF-BP is able to bind directly to FGF-2 without additional cofactors and to exhibit bioactivity. The purified recombinant FGF-BP stimulates tumor cell growth as well as endothelial cell growth and chemotaxis, indicating a dual growth-supporting role of FGF-BP in tumors. We show that this paracrine FGF-BP effect is dependent on endogenously expressed FGF-2, since it can be completely blocked by anti-FGF-2 antibodies. In tumor xenografts and in tumor cells, we detected a pattern of specific FGF-BP-immunoreactive high molecular weight forms, which presumably represent stable covalent complexes of FGF-BP and show marked differences in their occurrence in different tumors and in their heparin binding affinity. By providing further insight into the mechanism of FGF-BP action, our results emphasize the relevance of FGF-BP and of FGF-2 in tumor growth.
Aigner
A
A
Department of Pharmacology and Toxicology, Philipps-University Medical School, Marburg, Germany. aigner@mailer.uni-marburg.de
Butscheid
M
M
Kunkel
P
P
Krause
E
E
Lamszus
K
K
Wellstein
A
A
Czubayko
F
F
D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006031:Glycosylation; D006493:Heparin / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D013058:Mass Spectrometry; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014470:Umbilical Cord / Q000166:cytology
D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; C070699:FGFBP1 protein, human; D012965:Sodium Chloride; D006493:Heparin