Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro

Pepper, Michael Sean; Ferrara, Napoleone; Orci, Lelio; Montesano, Roberto

doi:10.1016/0006-291x(92)92277-5

Cited by 795 publications

(507 citation statements)

References 23 publications

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“…Importantly, when the assay was repeated in the presence of VEGF and FGF2, the number of tubules was enhanced 3-4 fold compared with beads cultured with VEGF alone (Figure 2c). These data are in agreement with previous reports showing that FGF2 can enhance VEGF-mediated angiogenesis (Pepper et al, 1992;Giavazzi et al, 2003). Sunitinib was also able to suppress tubule formation in the presence of VEGF and FGF2 (Figure 2c).…”

Section: Resultssupporting

confidence: 93%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

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The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.

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Section: Resultssupporting

confidence: 93%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

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“…Invasion was quantified by measuring the total additive length of all cells penetrating into the underlying gel to form cell cords. 38 The kinetics of FGF-2-induced invasion are more rapid and transient when compared with VEGF ( Figure 2I). 39 Figure 2D shows the behavior of bovine microvascular endothelial (BME) cells cocultured with mock-transfected C 2 C 12 cells.…”

Section: Resultsmentioning

confidence: 98%

“…Endothelial cells are cultivated on the surface of a threedimensional collagen gel 36 upon which they grow to form a confluent monolayer and do not invade the underlying matrix (Figure 2A, C). Treatment with an angiogenic factor such as FGF-2 37 or VEGF, 38 directly activates the endothelial cells and induces them to invade the underlying gel, forming branching and anastomosing cell cords (Figure 2B, E, G). Tube-like structures resembling capillaries can be observed beneath the surface monolayer.…”

Section: Resultsmentioning

confidence: 99%

“…Invasion was quantified from three randomly selected 1 × 1.4 mm fields per well, by measuring the total length of all cells which penetrated into the underlying gel either as single cells or in the form of cell cords. 38 Results are from at least three experiments, ie at least nine microscopic fields per condition (three measurements per experiment). Values are expressed as mean ± s.e.m.…”

Section: In Vitro Angiogenesis Assaymentioning

confidence: 99%

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Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

et al. 2001

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Stimulating angiogenesis by gene transfer approaches offers the hope of treating tissue ischemia which is untreatable by currently practiced techniques of vessel grafting and bypass surgery. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are potent angiogenic molecules, making them ideal candidates for novel gene transfer protocols designed to promote new blood vessel growth. In this study, an ex vivo gene therapy approach utilizing cell encapsulation was employed to deliver VEGF and FGF-2 in a continuous and localized manner. C(2)C(12) myoblasts were genetically engineered to secrete VEGF(121), VEGF(165) and FGF-2. These cell lines were encapsulated in hollow microporous polymer membranes for transplantation in vivo. Therapeutic efficacy was evaluated in a model of acute skin flap ischemia. Capsules were positioned under the distal, ischemic region of the flap. Control flaps showed 50% necrosis at 1 week. Capsules releasing either form of VEGF had no effect on flap survival, but induced a modest increase in distal vascular supply. Delivery of FGF-2 significantly improved flap survival, reducing necrosis to 34.2% (P < 0.001). Flap vascularization was significantly increased by FGF-2 (P < 0.01), with numerous vessels, many of which had a large lumen diameter, growing in the proximity of the implanted capsules. These results demonstrate that FGF-2, delivered from encapsulated cells, is more efficacious than either VEGF(121) or VEGF(165) in treating acute skin ischemia and improving skin flap survival. Furthermore, these data attest to the applicability of cell encapsulation for the delivery of angiogenic factors for the treatment and prevention of tissue ischemia

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“…u-PA mRNA expression in the parental sublines and Figure 3 Basic ®broblast growth factor has been shown to have important angiogenic effects in cancer. 4,8,13,22,28,33 bFGF stimulates endothelial cell proliferation and u-PA expression. 14 This facilitates matrix proteolysis for endothelial cell migration and neovascularization.…”

Section: Expression Of Tumor Necrosis Factor-amentioning

confidence: 99%