The oncogenic properties of the principal EBV oncoprotein, Latent Membrane Protein 1 (LMP-1), include the ability to induce invasiveness and metastasis factors. We have shown that LMP-1 induces matrix metalloproteinase 9 (MMP-9), a type IV collagenase that disrupts basement membrane. Also, cyclooxygenase-2 (COX-2), which is overexpressed in diverse malignancies, is induced by LMP-1; the enzyme is functional, and co-expressed with LMP-1 in NPC. Inhibitors of the NF kappa B signaling pathway, which is activated by LMP-1, including I kappa B super-repressor and aspirin reduce or cancel induction of MMP-9, COX-2 and invasiveness of LMP-1-expressing cells. Production of VEGF, also induced by LMP-1, is decreased by a COX-2-specific inhibitor. We now show that LMP-1 induces expression of the angiogenic Fibroblast Growth Factor-2 (FGF-2). Furthermore, LMP-1 also causes secretion of the 18 kDa isoform of this protein--a newly identified function for LMP-1. Secretion of FGF-2 is independently signaled through the NF-kappa B pathway. Release of the protein is not dependent on the classical ER/Golgi secretory pathway, but secretion of FGF-2 is suppressed by ouabain, an inhibitor of the Na+/K(+)-ATPase alpha 1 subunit. Finally LMP-1 induces expression of Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha), which mediates adaptation of cells to O2-depleted states. Thus LMP-1 is not only directly oncogenic, it can induce a constellation of factors that reveal the additional role of EBV in invasive cancers such as NPC. Alteration of cellular phenotype independent of transforming effects may be a property of other tumor viruses.