Human Fibroblast Growth Factor-Binding Protein HBp17 Enhances the Tumorigenic Potential of Immortalized Squamous Epithelial Cells

HBp17 (FGFBP-1), a secreted Mr17,000 heparin-binding protein, binds reversibly to acidic fibroblast growth factor (FGF-1) and to basic FGF (FGF-2). HBp17 is synthesized by normal human keratinocytes and by squamous carcinoma cells including highly tumorigenic A431 human epidermoid carcinoma cells. In this study we have examined the role of HBp17 in the tumorigenicity of A431 cells. HBp17 cDNA was cloned into an RSV LTR-driven expression vector and used to transfect A431-4, a non-tumorigenic A431 clonal variant that expresses FGF-1 and FGF-2 but not HBp17. A431-4-1 cells, which were transfected with HBp17 cDNA, produced palpable tumors in nude mice in 6–8 weeks, while empty vector transfectants formed no tumors in 14 weeks. Secondary and tertiary tumors derived from A431-4-1 cells were increasingly more tumorigenic than the original HBp17 cDNA transfectants. By northern blot analysis, the tumorigenicity of the A431-4 transfectants correlated with HBp17 mRNA expression levels and not with the levels of FGF-1 or FGF-2 transcripts. Higher levels of FGF-1 and FGF-2 were present in culture medium conditioned by A431-4-1 transfectants expressing HBp17 and their derivatives than in medium conditioned by non-tumorigenic A431-4-0 control cells. These results indicate that HBp17 potentiates the development of squamous cell carcinomas through its interactions with the two prototypic members of the fibroblast growth factor family. Since A431 cells are not growth stimulated by FGFs 1 or 2, the potentiation of tumor growth likely occurs through a paracrine rather than an autocrine mechanism.