Endothelial cells overexpressing basic fibroblast growth factor (FGF-2) induce vascular tumors in immunodeficient mice.
Basic fibroblast growth factor (FGF-2) is expressed in vascular endothelium during tumor neovascularization and angioproliferative diseases, including vascular tumors and Kaposi's sarcoma (KS). We have investigated the in vivo biological consequences of endothelial cell activation by endogenous FGF-2 in a mouse aortic endothelial cell line transfected with a retroviral expression vector harboring a human FGF-2 cDNA and the neomycin resistance gene. FGF-2 transfectants, named pZipbFGF2-MAE cells, caused the rapid growth of highly vascularized, non-infiltrating tumors when injected in nude mice. In contrast, lesions grew poorly when cells were injected in immunocompetent syngeneic animals. Histologically, the tumors had the appearance of hemangioendothelioma with spindled areas resembling KS and with numerous CD31+ blood vessels and lacunae. Southern blot analysis of tumor DNA, as well as disaggregation of the lesion followed by in vitro cell culture, revealed that less than 10% of the cells in the tumor mass retain FGF-2 overexpression and neomycin resistance at 6-8 weeks post-injection. Nevertheless, in vitro G418 selection allowed the isolation from the tumor of a FGF-2-overexpressing cell population showing biochemical and biological characteristics similar to those of pZipbFGF2-MAE cells, including the capacity to originate vascular lesions when re-injected in nude mice. To evaluate the effect of angiostatic compounds on the growth and vascularization of pZipbFGF2-MAE cell-induced lesions, nude mice were treated weekly (100mg/kg, i.p.) with the angiostatic sulfonated distamycin A derivative 2,2'-(carbonyl-bis-[imino-N-methyl-4,2-pyrrole carbonyl-imino-{N-methyl-4,2-pyrrole}carbonylimino])-bis-(1,5-naphthalene) disulfonic acid (PNU 153429). The results demonstrate that PNU 153429 inhibits the growth of the lesions and causes a approximately 50% decrease in CD31+ microvessel density. In conclusion, the data indicate that FGF-2-overexpressing endothelial cells cause vascular lesions in immunodeficient mice which may represent a novel model for opportunistic vascular tumors suitable for the evaluation of angiostatic compounds.