TY - JOUR
T1 - Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments
AU - Williams, Shanté P.
AU - Nowicki, Michal O.
AU - Liu, Fang
AU - Press, Rachael
AU - Godlewski, Jakub
AU - Abdel-Rasoul, Mahmoud
AU - Kaur, Balveen
AU - Fernandez, Soledad A.
AU - Chiocca, E. Antonio
AU - Lawler, Sean E.
PY - 2011/8/15
Y1 - 2011/8/15
N2 - Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that β-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in gliomabearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer.
AB - Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that β-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in gliomabearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=80051699521&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-3026
DO - 10.1158/0008-5472.CAN-10-3026
M3 - Article
C2 - 21697283
AN - SCOPUS:80051699521
SN - 0008-5472
VL - 71
SP - 5374
EP - 5380
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -