Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: Implications for tumor angiogenesis

Dorit Shweiki*, Michal Neeman, Ahuva Itin, Eli Keshet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

545 Scopus citations

Abstract

Perfusion insufficiency, and the resultant hypoxia, often induces a compensatory neovascularization to satisfy the needs of the tissue. We have used multicellular tumor spheroids, simulating avascular microenvironments within a clonal population of glioma tumor cells, in conjunction with in situ analysis of gene expression, to study stress inducibility of candidate angiogenic factors. We show that expression of vascular endothelial growth factor (VEGF) is upregulated in chronically hypoxic niches (inner layers) of the spheroid and that expression is reversed when hypoxia is relieved by hyperoxygenation. Acute glucose deprivation-another consequence of vascular insufficiency-also activates VEGF expression. Notably, glioma cells in two distinct regions of the spheroid upregulated VEGF expression in response to hypoxia and to glucose starvation. Experiments carried out in cell monolayers established that VEGF is independently induced by these two deficiencies. Upon implantation in nude mice, spheroids were efficiently neovascularized. Concomitant with invasion of blood vessels and restoration of normoxia to the spheroid core, VEGF expression was gradually downregulated to a constitutive low level of expression, representing the output of nonstressed glioma cells. These findings show that stress-induced VEGF activity may compound angiogenic activities generated through the tumor 'angiogenic switch' and suggest that stress-induced VEGF should be taken into account in any attempt to target tumor angiogenesis.

Original languageEnglish
Pages (from-to)768-772
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number3
DOIs
StatePublished - 31 Jan 1995

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