Export of FGF1 and FGF2

FGF-1 and FGF-2 lack a signal sequence, and the molecular pathway by which these growth factors are secreted from the cytoplasm to the extracellular space is not known (129). Two steps for the release of FGF-1 and FGF-2 from cells have to be considered: first, the actual translocation through the plasma membrane into the extracellular space; and, second, the release of FGF-1 and FGF-2 from their sequestration sites in the extracellular matrix and basement membranes.

Several reports provide evidence that export of FGF-1 and FGF-2 may involve a novel secretory pathway. Stably transfected NIH 3T3 cells, which expressed high levels of FGF-1, released inactive homodimers of FGF-1 on heat shock, in a process that required de novo synthesis of protein. This export was not prevented by Brefeldin A and methyl amine, inhibitors of ER-Golgi transport and exocytosis, respectively (130). Active export of FGF-2 in unusual high mol wt forms has been reported in cell lines derived from different stages of fibrosarcoma development in transgenic mice carrying the bovine papilloma virus genome (131). Cell lines established from the P-cell tumors of Rip1Tag2 transgenic mice (PTC) constitutively secreted FGF-1 into the culture medium (131a). Treatment of this medium with high salt recovered FGF-1 as high mol wt (HMW) forms with reduced heparin-affinity and a molecular mass of approx 40 kDa. Brefeldin A, an inhibitor of conventional secretion, did not interfere with FGF-1 export by P-tumor cells. In other established tumor cell lines, including human breast carcinoma and murine fibrosarcoma, a similar export of FGF-2 as HMW forms, with reduced heparin affinity, was detected. This did not hold true for normal or premalignant cell lines that expressed high levels of FGF-2 (131a). Collectively, these data strongly suggest that a similar, nonconventional pathway is utilized by different cell lines for the export of FGF-1 and FGF-2. Alternatively, FGF-1 could be bound as a heterodimer to another unknown partner to produce the observed HMW forms. One candidate for a partner protein that could associate with FGF-1 and FGF-2, to produce the ~40 kDa HMW forms, is a recently discovered FGF binding protein (FGF-BP) (132). Tumor cell growth and angiogenesis could be enhanced using gene transfection approaches to upregulate FGF-BP in tumor cells (132). Moreover, suppression of FGF-BP expression significantly blocked the growth of squamous cell carcinoma and colon carcinoma in nude mice (133). These data suggest that FGF-1 and FGF-2 are selectively exported by many tumor cell types, and also by normal cell types, under stress conditions or during physiological angiogenesis via a nonconventional secretory pathway. A switch in the subcellular localization of FGF may be a general mechanism of tumor promoted angiogenesis.

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