| Title | Bone marrow-derived endothelial progenitors expressing delta-like 4 (Dll4) regulate tumor angiogenesis |
| Publication Type | Journal Article |
| 2011 |
| Authors | Real, C, Remédio, L, Caiado, F, Igreja, C, Borges, C, Trindade, A, Pinto-Do-Ó, P, Yagita, H, Duarte, A, Dias, S |
| Journal | PLoS ONEPLoS ONE |
| Volume | 6 |
| Issue | 4 |
| Date Published | 2011/// |
| 19326203 (ISSN) |
| angiogenesis, animal, animal cell, animal tissue, Animals, apoptosis, article, blood vessel, Blood Vessels, bone marrow, bone marrow cell, Bone Marrow Cells, cell activation, Cell Line, Tumor, cell proliferation, controlled study, cytology, delta like 4 protein, DLL4 protein, mouse, Endothelial Cells, endothelium cell, Female, Fibronectin, gene expression, gene expression regulation, genetics, human, human cell, Humans, hypoxia, in vitro study, in vivo study, intercellular adhesion molecule 2, Intracellular Signaling Peptides and Proteins, membrane protein, Membrane Proteins, metabolism, Mice, mouse, Mus, neoplasm, Neoplasms, neovascularization (pathology), Neovascularization, Pathologic, neutralizing antibody, nonhuman, Notch receptor, Pathology, pericyte, protein expression, signal peptide, solid tumor, stem cell, stem cell transplantation, Stem cells, stromal cell derived factor 1, tumor cell line, tumor growth, unclassified drug, vascularization, vasculotropin |
| Neo-blood vessel growth (angiogenesis), which may involve the activation of pre-existing endothelial cells (EC) and/or the recruitment of bone marrow-derived vascular precursor cells (BM-VPC), is essential for tumor growth. Molecularly, besides the well established roles for Vascular endothelial growth factor (VEGF), recent findings show the Notch signalling pathway, in particular the ligand Delta-like 4 (Dll4), is also essential for adequate tumor angiogenesis; Dll4 inhibition results in impaired, non-functional, angiogenesis and reduced tumor growth. However, the role of BM-VPC in the setting of Notch pathway modulation was not addressed and is the subject of the present report. Here we show that SDF-1 and VEGF, which are produced by tumors, increase Dll4 expression on recruited BM-VPC. Mechanistically, BM-VPC activated, in a Dll4-dependent manner, a transcriptional program on mature EC suggestive of EC activation and stabilization. BM-VPC induced ICAM-2 and Fibronectin expression on EC, an effect that was blocked by a Dll4-specific neutralizing antibody. In vivo, transplantation of BM-VPC with decreased Dll4 into tumor-bearing mice resulted in the formation of microvessels with decreased pericyte coverage and reduced fibronectin expression. Consequently, transplantation of BM-VPC with decreased Dll4 resulted in impaired tumor angiogenesis, increased tumor hypoxia and apoptosis, and decreased tumor growth. Taken together, our data suggests that Dll4 expression by BM-VPC affects their communication with tumor vessel endothelial cells, thereby modulating tumor angiogenesis by affecting vascular stability. © 2011 Real et al. |
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