title: VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors.
abstract: We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors.
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Grun
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA, USA.|Departments of Dermatology, University of Maryland School of Medicine, Baltimore, MA, USA.|Departments of Reproductive Biology, University of Maryland School of Medicine, Baltimore, MA, USA.|Departments of Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, MA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000502:physiology*; D039942:Neuropilin-1 / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D012878:Skin Neoplasms / Q000098:blood supply / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor