Induction of Vascular Endothelial Growth Factor Expression by Hypoxia and by glucose Deficiency in Multicell Spheroids: Implications for Tumor Angiogenesis

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 an...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1995-01, Vol.92 (3), p.768-772
Main Authors: Shweiki, Dorit, Neeman, Michal, Itin, Ahuva, Keshet, Eli
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Cell growth
Cell Hypoxia
Cell lines
Cellular biology
Endothelial Growth Factors - biosynthesis
Endothelial Growth Factors - genetics
Gene expression regulation
Gene Expression Regulation, Neoplastic - drug effects
Genes
Glioma
Glioma - blood supply
Glioma - metabolism
Glioma - pathology
Glucose - pharmacology
Glucose - physiology
Hypoxia
Lymphokines - biosynthesis
Lymphokines - genetics
Messenger RNA
Mice
Mice, Nude
Neoplasm Transplantation
Neovascularization, Pathologic - pathology
Oxygen
Oxygen - pharmacology
Rats
RNA, Messenger - biosynthesis
Spheroids
Tumor Cells, Cultured
Tumors
Up-Regulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.92.3.768