title: Tumor gangliosides accelerate murine tumor angiogenesis.
abstract: Tumor cells shed gangliosides and populate their microenvironment with these biologically active membrane glycosphingolipids. In vitro, ganglioside enrichment amplifies receptor tyrosine kinase signaling and activation of vascular endothelial cells. However, a long-standing question is whether in the actual microenvironment of a neoplasm, in vivo, tumor cell ganglioside shedding stimulates angiogenesis. Here we tested the hypothesis that tumor gangliosides have a critical proangiogenic role in vivo using novel murine tumor cells, GM3synthase/GM2synthase double knockout (DKO) cells, genetically completely incapable of ganglioside synthesis and impaired in tumor growth versus wild-type (WT) ganglioside-rich cells. We studied angiogenesis during tumor formation by these ganglioside-depleted cells, quantifying vessel formation, angiogenic factor production/release, and consequences of reconstitution with purified WT gangliosides. DKO cells formed virtually avascular tumors, much smaller than ganglioside-rich WT tumors and displaying a striking paucity of blood vessels, despite levels of VEGF and other angiogenic factors that were similar to those of WT cells. Transient enrichment of the ganglioside milieu of the DKO cell inoculum by adding purified WT gangliosides partially restored angiogenesis and tumor growth. We conclude that tumor gangliosides trigger robust angiogenesis important for tumor growth. Our findings suggest strategies to eliminate their synthesis and shedding by tumor cells should be pursued.
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC, 20010, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Liu
authors.forename: Assefa
authors.initials: A
authors.lastname: Wondimu
authors.forename: Su
authors.initials: S
authors.lastname: Yan
authors.forename: Daniel
authors.initials: D
authors.lastname: Bobb
authors.forename: Stephan
authors.initials: S
authors.lastname: Ladisch
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005732:Gangliosides / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D005732:Gangliosides; D042461:Vascular Endothelial Growth Factor A