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Modes of FGF release in vivo and in vitro

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Summary

The fibroblast growth factors (FGFs) are a family of polypeptide growth regulators. The prototypes of this family are acidic and basic FGF. Unusual among their characteristics are a high affinity for the glycosaminoglycan heparin and the lack of a signal sequence for secretion. Other members of the FGF family include a number of oncogene products that also display heparin affinity but do possess signal sequences. Results from early tissue culture studies were consistent with the prediction that acidic and basic FGF would not be secreted. Investigators found that virtually no FGF was secreted into conditioned media, instead it remained cell-associated and was deposited into the basement membrane. More recently, however, a number of studies have indicated that a small amount of FGF is ‘released’ from cells where it is postulated to act as an autocrine regulator. Acidic and basic FGF have been localized in basement membranes bothin vivo andin vitro. The mode of release to this site is also unclear but may be secondary to the mechanisms cited above with soluble FGF becoming bound to heparan sulfate molecules in the extracellular matrix. A number of observations have indicated that matrix-bound FGF is biologically activein vitro. There are no data to indicate whether the same is true for FGF bound to basement membranesin vivo. In addition to its apparent sequestration in the basement membrane, FGF has also been localized to the surface of a variety of normal and tumor cell types. In particular, endothelial cells have been shown to possess two classes of FGF-binding sites: low abundance, high-affinity receptors that mediate the biological activity as well as high abundance, low affinity binding sites. The physiologic relevance of FGF binding to these low affinity sites is not clear. The possibility of locally high concentrations of heparin released by mast cells, as well as the presence of heparan sulfate-degrading enzymes, suggests that this glycosaminoglycan bound FGF might be released from these binding sites under some circumstances. Cell surface binding of FGF has also been demonstratedin vivo; in rabbits plasma levels of the growth factor were shown to be dramatically elevated following intravenous heparinization. Since the FGFs were first noted to lack a signal sequence, cell injury has been suspected to be the most likely route for FGF releasein vivo. A number of studies using different models of cell injury, including endotoxins and irradiation, have revealed that damaged cells do release FGF. Whether cell death is actually necessary for FGF release was addressed in an experiment in which transient cell injury was caused by cell scraping. These studies revealed that FGF could be released by non-lethal cell injury. The mechanism by which FGF is released to the basement membrane, cell surface and extracellular space is not clear and may be accounted for by cell leakage, cell death, sublethal cell injury, a novel secretion pathway or any combination of these. Identification of the means of FGF release may provide insight into the physiologic role of acidic and basic FGF. Further, it may help to elucidate the mode of release of other biologically active molecules known not to contain signal sequences, including interleukin 1 and platelet-derived endothelial cell growth factor.

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  1. Laboratory for Surgical Research, Children's Hospital, 02115, Boston, MA, USA

    Patricia A. D'Amore

  2. Department of Pathology, Harvard Medical School, 02115, Boston, MA, USA

    Patricia A. D'Amore

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D'Amore, P.A. Modes of FGF release in vivo and in vitro. Cancer Metast Rev 9, 227–238 (1990). https://doi.org/10.1007/BF00046362

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