Nuclear FGF-2 facilitates cell survival in vitro and during establishment of metastases.

Abstract

Nuclear-targeted high molecular weight 24 kDa fibroblast growth factor 2 (FGF-2) may induce specific cell functions through intracrine mechanisms. The role of nuclear FGF-2 on the metastatic potential of carcinoma cells was examined by conditional FGF-2 expression, which demonstrated that spontaneous metastasis in nude mice is a direct consequence of its expression. The lung colonizing capacities of fluorescent nuclear FGF-2-expressing cells following intravenous injection was also investigated. All cells reaching the lung extravasated as soon as 5 min following injection with similar in vivo behavior during the first 24 h. However, after 2 days, dramatic differences were observed between the FGF-2 and parental cells: most control cells underwent apoptosis, while the FGF-2-producing cells instigated a survival program and proliferated. Therefore, sustained apoptosis in vivo prevents growth of metastatic foci, while nuclear FGF-2 induction of a survival program is responsible for growth of the lung metastases. In vitro serum deprivation assays also established that 24 kDa FGF-2 expression improves carcinoma cell survival. This study provides both in vitro and in vivo evidence that the role of the nuclear 24 kDa FGF-2 isoform in carcinoma is the promotion of cell survival, thereby defining its association with poor prognosis in some human carcinomas.