Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis.
Tumors express more than a single angiogenic growth factor. To investigate the relative impact of fibroblast growth factor-2 ( FGF-2) and vascular endothelial growth factor ( VEGF) on tumor growth and neovascularization, we generated tumor cell transfectants differing for VEGF and/or FGF-2 expression. Human endometrial adenocarcinoma HEC-1-B-derived Tet- FGF-2 cells that express FGF-2 under the control of the tetracycline-responsive promoter (Tet-off system) were further transfected with a VEGF(121) anti-sense (AS- VEGF) cDNA. Next, Tet- FGF-2 and AS-VEGF/Tet- FGF-2 cells were transplanted subcutaneously in nude mice that received tetracycline or not in the drinking water. Simultaneous expression of FGF-2 and VEGF in Tet- FGF-2 cells resulted in fast-growing lesions characterized by high blood vessel density, patency and permeability, and limited necrosis. Blood vessels were highly heterogeneous in size and frequently associated with pericytes. Inhibition of FGF-2 production by tetracycline caused a significant decrease in tumor burden paralleled by a decrease in blood vessel density and size. AS-VEGF expression resulted in a similar reduction in blood vessel density associated with a significant decrease in pericyte organization, vascular patency, and permeability. The consequent decrease in tumor burden was paralleled by increased tumor hypoxia and necrosis. A limited additional inhibitory effect was exerted by simultaneous down-regulation of FGF-2 and VEGF expression. These findings demonstrate that FGF-2 and VEGF stimulate vascularization synergistically but with distinctive effects on vessel functionality and tumor survival. Blockade of either one of the two growth factors results in a decrease in blood vessel density and, consequently, in tumor burden. However, inhibition of the expression of VEGF, but not of FGF-2, affects also vessel maturation and functionality, leading to tumor hypoxia and necrosis. Our experimental model represents an unique tool to investigate anti-neoplastic therapies in different angiogenic environments.[1]References
- Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Giavazzi, R., Sennino, B., Coltrini, D., Garofalo, A., Dossi, R., Ronca, R., Tosatti, M.P., Presta, M. Am. J. Pathol. (2003) [Pubmed]
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