Impact on tumor angiogenesis and tumor progression of expression of the 18kD and 24 kD isoforms of FGF-2.

The role of FGF-2 in tumor progression and tumor cell invasiveness was inve stigated using the rat bladder carcinoma cells NET-II, which do not constit utively express FGF-2 or its membrane-spanning receptor. The NET-II cells w ere transfected using expression vectors encoding either the 18 kD or the 2 4 kD isoform of FGF-2, The 24 kD isoform contains a nuclear localization si gnal. The transfected NET-II cells that expressed 18 kD FGF-2 produced and secreted this factor as the biologically active form and retained an epithe lial morphology. When injected to nude mice, the tumorigenic potential of t hese cells was not increased over that of non-transfected NET-II cells; how ever, although the time to tumor development was long, the tumors were high ly vascularized indicating secretion of the angiogenic factor FGF-2, The tr ansfected NET-II cells that expressed 24 kD FGF-2 varied in their morpholog ical appearance and did not secrete FGF-2; immunofluorescence and Western-b lot studies showed that the FGF-2 was mainly intranuclear. When injected to nude mice, these cells produced tumors and migrated not only to the lymph nodes but also to the lungs where they produced metastases. In aggregate, t hese data indicate that stimulation of angiogenesis is not sufficient to in crease tumor growth and that nuclear FGF-2 acts as a tumorigenic and metast asis-promoting factor in the NET-II carcinoma model.