title: Vascular channels formed by subpopulations of PECAM1+ melanoma cells.
abstract: Targeting the vasculature remains a promising approach for treating solid tumours; however, the mechanisms of tumour neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally derived PECAM1(+) tumour cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, vascular endothelial growth factor (VEGF)-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1(+) melanoma cells and is a transcriptional repressor of PECAM1. Re-introduction of AP-2α into PECAM1(+) tumour cells represses PECAM1 and abolishes tube-forming ability, whereas AP-2α knockdown in PECAM1(-) tumour cells upregulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumour, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Dunleavey
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Mi Mi
authors.initials: MM
authors.lastname: Kim
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Janiel M
authors.initials: JM
authors.lastname: Shields
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Shelton
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Irvin
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Brings
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Ollila
authors.affiliation: Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas 75235, USA.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dayton
authors.affiliation: Department of Cardiac Surgery, Harvard Medical School and Children's Hospital Boston, Boston, Massachusetts 02115, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Melero-Martin
authors.affiliation: 1] Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [3] McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Dudley
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2