Membrane ganglioside enrichment lowers the threshold for vascular endothelial cell angiogenic signaling.
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.
Liu
Yihui
Y
Center for Cancer and Immunology Research, Children's National Medical Center, The George Washington University School of Medicine, Washington, District of Columbia 20010-1970, USA.
McCarthy
James
J
Ladisch
Stephan
S
D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D005732:Gangliosides / Q000502:physiology*; D006801:Humans; D008563:Membrane Lipids / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D005732:Gangliosides; D008563:Membrane Lipids; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2