Extracellular matrix‐resident basic fibroblast growth factor: Implication for the control of angiogenesis

Vlodavsky, Israël; Fuks, Zvi; Ishai-Michaeli, Rivka; Bashkin, Pnina; Levi, Ehud; Korner, Gil; Bar-Shavit, Rachel; Klagsbrun, Michael

doi:10.1002/jcb.240450208

Cited by 268 publications

(150 citation statements)

References 37 publications

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“…Stimulation of cell proliferation by intracellularly acting ®broblast growth factors was earlier observed in nonglial cells. In ®broblasts the mitogenic e ects of extracellular FGF-1 require nuclear translocation of the growth factor and can be separated from its ability to stimulate cell membrane receptors (Imamura et al, 1990;Wiedlocha et al, 1994). Our ®ndings are also consistent with those of Bikfalvi et al (1995) who showed that intracellularly expressed high molecular weight FGF-2 isoforms stimulate proliferation of ®broblasts independent of their surface receptors.…”

Section: Exocrine and Intracrine Action Of Fgf-2supporting

confidence: 88%

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

et al. 1997

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FGF-2 has been implicated in the neoplastic transformation of glioma cells and in the transition of normal quiescent astrocytes to a proliferating, reactive state. In the present study we have observed that in human glial cells, levels and subcellular localization of FGF-2 are di erent in quiescent and proliferating cells. FGF-2 was detected in the cytoplasm of non-reactive astrocytes in human brain sections. In contrast FGF-2 was located within the cytoplasm and nuclei of reactive astrocytes in gliotic brain tissue and in neoplastic cells of glioma tumors. In vitro, FGF-2 was found predominantly in the nucleus of subcon¯uent proliferating astrocytes, but was detected only in the cytoplasm of density arrested quiescent astrocytes. Our results suggest that reduced cell contact stimulates nuclear accumulation of FGF-2, accompanying mitotic activation of reactive human astrocytes. FGF-2 was constitutively localized to the nucleus of continuously proliferating glioma cells independent of cell density. A role for intracellular FGF-2 was further suggested by the observation that glioma cells that are not stimulated to proliferate by extracellular FGF-2 proliferated faster when transfected with FGF-2 expressing vectors. This increased proliferation correlated with nuclear accumulation of FGF-2. Cell proliferation was attenuated by 5'-deoxy-5'-methylthioadenosine, a FGF-2 receptor tyrosine kinase inhibitor that acts within the cell, but was una ected by myo-inositol hexakis [dihydrogen phosphate] that disrupts FGF-2 binding to plasma membrane receptors. Our results indicate that FGF-2 serves as a nuclear regulator of proliferation in astrocytic cells. In glioma cells, the constitutive presence of FGF-2 in the nucleus may promote proliferation that is insensitive to cell contact inhibition.

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Section: Exocrine and Intracrine Action Of Fgf-2supporting

confidence: 88%

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

et al. 1997

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“…Our finding that hypoxic percentages remain low for some time after cessation of FGF-2 administration would be consistent with a sustained FGF-2 induced increase in overall vascular capability, which may be due to FGF-2 binding by the tumour extracellular matrix during administration (e.g. heparan sulfate proteoglycans), with subsequent gradual release of bound FGF-2 by heparinase and other proteolytic enzymes (Flaumenhaft et al, 1989(Flaumenhaft et al, , 1990Folkman et al, 1988;Vlodavsky et al, 1991). It is fortuitous that, in our choice of DLD-2 neoplasms to study FGF-2 related changes in intratumour hypoxia, DLD-2 cells contain low levels of FGF-2.…”

Section: Discussionsupporting

confidence: 76%

Effects of administration of basic fibroblast growth factor on hypoxic fractions in xenografted DLD-2 human tumours: time dependence

Leith

Michelson²

1993

Br J Cancer

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Summary A previous publication (Leith et al., 1992) showed that administration of basic fibroblast growth factor 0.25 We recently reported in this journal that administration of basic fibroblast growth factor (FGF-2; q.i.d. x 7; 0.25 mg kg-') caused a significant increase in the growth rates of xenografted DLD-2 human colon cancers, and concomitantly decreased the percentage of hypoxia within these neoplasms (Leith et al., 1992). In that study, hypoxia levels were determined 1 day after the end of a 7 day period of FGF-2 administration, at a time when the volumes of control (given sham-injections with Hank's balanced salt solution) or FGF-2 treated tumours had increased from 211 mm3 to 992 and 1751 mm3 respectively. Although the FGF-2 treated tumours were about 1.8 times the volume of controls at the time of assay, the percentage of hypoxia within these neoplasm was 19.1% (13.5-26.9; 95% confidence limits) whereas the percentage in control neoplasms was 42.2% (34.2-52.1). In essence, increases in tumour volume can be uncoupled from changes in hypoxia by FGF-2 administration. In these studies however, the effects of the nonequivalent tumour volumes on interpretation of steady-state levels of hypoxia as a function of volume were not explicitly studied.Because of our lack of knowledge of how steady-state levels of hypoxia within unperturbed DLD-2 tumours might change as a function of volume, we performed further experiments to define these kinetics. Additionally, we examined hypoxia levels in FGF-2 treated DLD-2 tumours at several times during and after the administration of growth factor. Materials and methods Cell lineThe biological characteristics of the DLD-2 cell line have been previously described (Leith et al., 1992). For these experiments, stock cells stored in liquid nitrogen were grown in RPMI-1640 medium containing 10% foetal bovine serum (FBS), 1% sodium bicarbonate, 1% anti-PPLO reagent, 1% 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, and 0.04% gentamicin (all reagents from the Grand Island Biological Co., Grand, Island, NY).Mice and production of xenografted tumours Young adult male mice were obtained from the Charles River Breeding Laboratories, North Wilmington, MA. Mice were housed, five per large cage, with dust covers, in a dedicated room in the Brown University Animal Care Facilities in a laminar flow hood (Thoren Industries, King of Prussia, PA). Mice were quarantined for 1 week, and were ear tagged for identification. To produce tumours (one tumour per animal), DLD-2 cells were trypsinised (0.05% trypsin, 0.54 mM EDTA) from exponentially growing cultures, and resuspended as single cells in Hank's basic salt solution (HBSS) at a concentration of 5 x 107 cells ml-'. Nought point two ml of the cell suspension was injected into the right flank regions of the mice.Volumetric procedures Tumours were measured in two orthogonal diameters and volumes (mm3) were calculated using the formula for a prolate ellipsoid [V (mm3) = L x W2/2] where L and W are respectively the major and minor d...

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“…It is now evident that the ECM provides a storage depot for growth factors (e.g. bFGF, TGFfl) [3,4], enzymes (e.g. tPA, uPA) [5,6], enzyme inhibitors (e.g.…”

Section: Introductionmentioning

confidence: 99%

The extracellular matrix produced by bovine corneal endothelial cells contains progelatinase A

Ménashi¹,

Vlodavsky²,

Ishai-Michaeli³

et al. 1995

FEBS Letters

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Progelatinase A is a matrix metalloproteinase involved in the turnover of extracellular matrix (ECM). We report that the ECM produced by bovine corneal endothelial (BCE) cells contains progelatinase A free of tissue inhibitor of metalloproteinase (TIMP2). The matrix-bound progelatinase A can be activated by APMA to generate a 62 kDa and a 45 kDa species with enzymatic activity and is inhibited by TIMP2. The bound progelatinase can be released after treatment of the ECM with gelatinase B. These studies suggest that the ECM can function as a reservoir for progelatinase A which may be readily available for cells in processes such as metastasis, angiogenesis, inflammation and wound heating.

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Extracellular matrix‐resident basic fibroblast growth factor: Implication for the control of angiogenesis

Cited by 268 publications

References 37 publications

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

Effects of administration of basic fibroblast growth factor on hypoxic fractions in xenografted DLD-2 human tumours: time dependence

The extracellular matrix produced by bovine corneal endothelial cells contains progelatinase A

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