Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells

Abstract

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a mitogen and chemotactic factor for endothelial cells in vitro and an angiogenesis and vascular permeability factor in vivo. Due to its properties, VEGF is a candidate for both angiogenesis and vascular permeability/oedema induction which typically occur in glioblastomas. In this study we test the hypothesis that the antioedema effect of dexamethasone is mediated by downregulation of VEGF or VEGF receptor expression. VEGF mRNA and protein levels of two rat glioma cells lines, C6 and GS-9L, were determined after incubation with dexamethasone under normoxic and hypoxic conditions. In normoxic C6 and GS9L cells, we observed 50-60% downregulation of VEGF mRNA by dexamethasone (P=0.015 and P=0. 01, respectively). This effect was dependent on glucocorticoid-receptor (GR) function. The inhibitory effect of dexamethasone on VEGF gene expression by tumour cells was markedly reduced by hypoxia which suggests that the upregulation of VEGF driven by hypoxia overcomes the effect of the dexamethasone. Dexamethasone did not alter VEGFR-2 mRNA levels in human umbilical endothelial cells. In a subcutaneous glioma tumour model, we observed only a 15% decrease in VEGF mRNA expression in dexamethasone treated animals (n = 12) compared with controls animals (P = 0.24). We conclude that dexamethasone may decrease brain tumour-associated oedema by reduction of VEGF expression in tumour cells. However, the highly reduced activity on hypoxic tumour cells suggests that dexamethasone efficacy may be limited by hypoxia in rapidly growing tumours.

Differential expression of VEGF receptors in adrenal atrophy induced by dexamethasone: a protective role of ACTH

“…Thus, from these experiments, we conclude that, among the VEGF receptors expressed in mouse adrenal, Flk-1/KDR is under the control of ACTH, and Flt-1 remained at a steady-state cAMP stimulates Flk-1/KDR expression in vitro in cultured ACE cells. A paracrine communication involving growth of blood vessels has been shown to play an important role during follicle maturation in the ovary and in the endometrium (29). Accordingly, our in vivo data imply that, during adrenal atrophy, a paracrine mechanism may be responsible for ACTH-dependent control of endothelial cells.…”

“…As an example, in lung no variations in VEGF expression were found (4), whereas several in vitro studies showed that dexamethasone strongly downregulates and/or inhibits induction of VEGF (34,46). However, in rat glioma cells, it has been shown that dexamethasone induced a differential downregulation of VEGF under normoxic and hypoxic conditions (29). In adrenal in vivo, the effect of dexamethasone was the result of a decreased level of endogenous ACTH, since animals receiving simultaneous administration of ACTH and dexamethasone did not present adrenal atrophy (data not shown).…”

Neuroendocrine influences on cancer biology

“…Dexamethasone (a synthetic glucocorticoid) treatment of cancer cells resulted in a 50-60% downregulation of VEGF mRNA in a rat glioma model, and this effect was dependent on the glucocorticoid receptor function. This inhibitory effect by dexamethasone was markedly reduced by hypoxia, which is a known inducer of VEGF [58]. In ovarian cancer cell lines, cortisol had limited stimulating effects at lower doses and inhibitory effects at pharmacologic doses.…”

Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells

“…1,2,8 -11 However, only a few factors that inhibit VEGF production have been identified. [11][12][13] In the present study, we evaluated the potency of the tetradecapeptide somatostatin (SS) and synthetic SS derivatives as negative regulators of VEGF production in glioma cells for the following reasons: (i) in several physiological systems, SS has antisecretory effects, e.g., inhibiting the production/release of growth hormone in pituitary cells, of insulin and glucagon in pancreatic ␤ and ␣ cells; (ii) SS receptors (sst), especially the subtype sst2, of these G protein-coupled, 7-transmembrane domain receptors, are frequently over-expressed in gliomas 14 -16 and thus render them susceptible to the endogenous or pharmacological action of SS or synthetic agonists.…”