Vascular permeability induced by protein product of malignant brain tumors: inhibition by dexamethasone

Abstract

Serum-free conditioned medium derived from confluent monolayer cultures of malignant human astroglial tumors contains a substance that rapidly increases capillary vascular permeability after intradermal injection into guinea pigs. Accumulation of vascular permeability factor (VPF) activity occurs with increasing duration of tumor incubation in vitro. Expression of this activity is inhibited by incubation of cell cultures with cycloheximide or dexamethasone. This VPF is an acid-stable heat-labile macromolecule that is inactivated by trypsin and pepsin and binds immobilized heparin. Activity is retained by ultrafiltration with 30,000-dalton cut-off microconcentrators. Pretreatment of test animals with systemic dexamethasone prior to intradermal injection of VPF diminishes microvascular permeability. Furthermore, VPF activity is not inhibited by antihistamines. Secretion of VPF may cause the vasogenic brain edema that is frequently associated with malignant primary and metastatic intracerebral tumors. Inhibition by dexamethasone of both VPF expression in tissue culture, and VPF activity at the microvascular level in test animals, is in keeping with the known efficacy of this agent in treating the vasogenic edema associated with brain tumors.

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

“…To establish whether dexamethasone inhibits the permeability induced by intradermal injection of 9LCM or recVPF, rats were treated with various doses of dexamethasone 6 h before the Miles assay. Previous work in our laboratory demonstrated effective suppression of permeability with dexamethasone given 6 h before the Miles assay in guinea pigs (19). The vascular permeability induced by either 9LCM or recVPF was reduced in a dose-dependent manner by dexamethasone (Fig.…”

“…Vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) has been shown to be a likely mediator of increased vascular permeability in some models of peripheral tumors (17,18), and the VPF secreted by glioma cells has been proposed to play the same role in brain tumors (19,20). Although VPF expression is clearly increased in response to hypoxia in rat C6 gliomaderived cells (21,22), the regulation of VPF in glioma cells by other inducers or by dexamethasone has not been well studied, although evidence exists that such regulation may occur in human glioma cells (19,23). In addition, dexamethasone has been shown to interfere with the early effects of VPF on endothelial cells (24).…”

VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain

“…It is interesting to note that dexamethasone, used for the treatment of cerebral edema associated with neoplasia, has been shown to inhibit the biological activity of VEGF (21)(22)(23). Because dexamethasone is known to be efficacious in reducing the formation of brain edema in animal models of stroke, it is interesting to speculate that the observed protective effect of dexamethasone may be mediated through its action on VEGF.…”

Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms.

“…In addition, tumor vessels often lack the tight junctions that are normally present in cerebral microvessels and that constitute a major barrier to the development of vasogenic edema (22)(23)(24). The release of vasoactive substance(s) by the tumor cells may also contribute to the development of vasogenic cerebral edema by direct actions on the tumor-associated endothelium (25,26). A human glioblastoma multiforme (GBM)-derived vascular permeability factor with characteristics similar to VEGPF has been previously described by this laboratory and proposed as a mediator of brain tumor-associated hyperpermeability (26,27).…”

“…The release of vasoactive substance(s) by the tumor cells may also contribute to the development of vasogenic cerebral edema by direct actions on the tumor-associated endothelium (25,26). A human glioblastoma multiforme (GBM)-derived vascular permeability factor with characteristics similar to VEGPF has been previously described by this laboratory and proposed as a mediator of brain tumor-associated hyperpermeability (26,27). The possibility that this GBM-derived permeability factor is VEGPF, and the potential association of VEGPF with the development of CNS tumor vascularity and vasogenic edema, prompted this investigation.…”