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Membrane Ganglioside Enrichment Lowers the Threshold for Vascular Endothelial Cell Angiogenic Signaling

¹ Center for Cancer and Immunology Research, Children's National Medical Center and Department of Pediatrics and Biochemistry/Molecular Biology, The George Washington University School of Medicine, Washington, District of Columbia and ² Department of Laboratory Medicine and Pathology and Comprehensive Cancer Center, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Stephan Ladisch, Center for Cancer and Immunology Research, Children's National Medical Center, 111 Michigan Avenue, Northwest, Washington, DC 20010-2970. Phone: 202-884-3883; Fax: 202-884-3929; E-mail: sladisch{at}cnmc.org.

Malignant tumor progression depends on angiogenesis, requiring vascular endothelial cell migration, and proliferation, triggered by tumor-derived vascular endothelial cell growth factor (VEGF). We show that gangliosides, which are actively shed by tumor cells and bind to normal cells in the tumor microenvironment, have the potential to sensitize vascular endothelial cells to respond to subthreshold levels of VEGF: Ganglioside enrichment of human umbilical vein vascular endothelial cells (HUVEC) caused very low, normally barely stimulatory, VEGF concentrations to trigger robust VEGF receptor dimerization and autophosphorylation, as well as activation of downstream signaling pathways, and cell proliferation and migration. Thus, by dramatically lowering the threshold for growth factor activation of contiguous normal stromal cells, shed tumor gangliosides may promote tumor progression by causing these normal cells to become increasingly autonomous from growth factor requirements by a process that we term tumor-induced progression of the microenvironment. (Cancer Res 2006; 66(21): 10408-14)

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