TY - JOUR
T1 - Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids
T2 - Implications for tumor angiogenesis
AU - Shweiki, Dorit
AU - Neeman, Michal
AU - Itin, Ahuva
AU - Keshet, Eli
PY - 1995/1/31
Y1 - 1995/1/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0028870050&partnerID=8YFLogxK
U2 - 10.1073/pnas.92.3.768
DO - 10.1073/pnas.92.3.768
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C2 - 7531342
AN - SCOPUS:0028870050
SN - 0027-8424
VL - 92
SP - 768
EP - 772
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 3
ER -