title: Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments.
abstract: 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 glioma-bearing 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.
authors.affiliation: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Shanté P
authors.initials: SP
authors.lastname: Williams
authors.forename: Michal O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Rachael
authors.initials: R
authors.lastname: Press
authors.forename: Jakub
authors.initials: J
authors.lastname: Godlewski
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abdel-Rasoul
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D038362:Glycogen Synthase Kinase 3; C027185:indirubin