Basic fibroblast growth factor overexpression in endothelial cells: an autocrine mechanism for angiogenesis and angioproliferative diseases.
Basic fibroblast growth factor (bFGF) is expressed in vascular endothelium during tumor neovascularization and angioproliferative diseases. The ultimate significance of this observation is poorly understood. We have investigated the biological consequences of endothelial cell activation by endogenous bFGF in a mouse aortic endothelial cell line stably transfected with a retroviral expression vector harboring a human bFGF cDNA. Selected clones expressing M(r) 24,000, M(r) 22,000, and/or M(r) 18,000 bFGF isoforms were characterized by a transformed morphology and an increased saturation density. bFGF transfectants showed invasive behavior and sprouting activity in three-dimensional fibrin gels and formed a complex network of branching cord-like structures connecting foci of infiltrating cells when seeded on laminin-rich basement membrane matrix (Matrigel). The invasive and morphogenetic behavior was prevented by anti-bFGF antibody, revealing the autocrine modality of the process. The biological consequences of this autocrine activation were investigated in vivo. bFGF-transfected cells gave rise to highly vascularized lesions resembling Kaposi's sarcoma when injected in nude mice and induced angiogenesis in avascular rabbit cornea. When injected into the allantoic sac of the chick embryo, they caused an increase in vascular density and formation of hemangiomas in the chorioallantoic membrane. In conclusion, bFGF-overexpressing endothelial cells acquired an angiogenic phenotype and recruit quiescent endothelium originating angioproliferative lesions in vivo. These findings demonstrate that bFGF overexpression exerts an autocrine role for endothelial cells and support the notion that tumor neovascularization and angioproliferative diseases can be triggered by stimuli that induce vascular endothelium to produce its own autocrine factor(s).
Gualandris
A
A
Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.
Rusnati
M
M
Belleri
M
M
Nelli
E E
EE
Bastaki
M
M
Molinari-Tosatti
M P
MP
Bonardi
F
F
Parolini
S
S
Albini
A
A
Morbidelli
L
L
Ziche
M
M
Corallini
A
A
Possati
L
L
Vacca
A
A
Ribatti
D
D
Presta
M
M
D016475:3T3 Cells / Q000166:cytology / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000166:cytology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002472:Cell Transformation, Viral; D002642:Chick Embryo; D003094:Collagen / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004338:Drug Combinations; D004728:Endothelium, Corneal / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D005109:Extracellular Matrix; D005337:Fibrin / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D006801:Humans; D007275:Injections, Intravenous; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008854:Microscopy, Electron; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010063:Ovum / Q000648:ultrastructure; D011509:Proteoglycans / Q000494:pharmacology; D011817:Rabbits; D012190:Retroviridae / Q000235:genetics
D018076:DNA, Complementary; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D005337:Fibrin; D003094:Collagen