期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6200
关键词
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资金
- National Institutes of Health [R00-CA140708, R01-CA177875, F31 CA174245, R01-CA170665]
- University Cancer Research Fund at UNC Chapel Hill
- NIH [S10-OD010410]
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-2 alpha is diminished in PECAM1(+) melanoma cells and is a transcriptional repressor of PECAM1. Re-introduction of AP-2 alpha into PECAM1(+) tumour cells represses PECAM1 and abolishes tube-forming ability, whereas AP-2 alpha 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.
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