ABSTRACT

Tumors express more than a single angiogenic growth factor. To investigate the relative impact of fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF) on tumor growth and neovascularization, we generated tumor cell transfectants differing for VEGF and/or FGF2 expression.

Human endometrial adenocarcinoma HEC-1-B-derived Tet-FGF2 cells that express FGF2 under the control of the tetracycline-responsive promoter (Tet-off system) were further transfected with a VEGF121 antisense (AS-VEGF) cDNA. Next, Tet-FGF2 and AS-VEGF/Tet-FGF2 cells were transplanted s.c. in nude mice that received tetracycline or not in the drinking water.

Simultaneous expression of FGF2 and VEGF in Tet-FGF2 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 FGF2 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 FGF2 and VEGF expression. (Click here for a graphic description of Tet-FGF2 and AS-VEGF/Tet-FGF2 tumors)

These findings demonstrate that FGF2 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 FGF2, affects also vessel maturation and functionality, leading to tumor hypoxia and necrosis. Our experimental model represents an unique tool to investigate antineoplastic therapies in different angiogenic environments.
 

Am. J. Pathol., 162: 1913-1926 (2003)