Bone Marrow-Derived Endothelial Progenitors Expressing Delta-Like 4 (Dll4) Regulate Tumor Angiogenesis

• Published in: PloS one Vol. 6; no. 4; p. e18323
• Main Authors: Real, Carla, Remédio, Leonor, Caiado, Francisco, Igreja, Cátia, Borges, Cristina, Trindade, Alexandre, Pinto-do-Ó, Perpétua, Yagita, Hideo, Duarte, Antonio, Dias, Sérgio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.04.2011; Public Library of Science (PLoS)
• Subjects: Activation; Angiogenesis; Animals; Apoptosis; Blood vessels; Blood Vessels - metabolism; Blood Vessels - pathology; Bone marrow; Bone Marrow Cells - cytology; Breast cancer; Cell Line, Tumor; Cell Proliferation; Cytokines; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelium; Fibronectin; Fibronectins; Gene expression; Gene Expression Regulation; Hemopoiesis; Humans; Hypoxia; Intracellular Signaling Peptides and Proteins - genetics; Laboratories; Ligands; Medicine; Membrane Proteins - genetics; Mice; Neoplasms - blood supply; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Neovascularization; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Notch protein; Oncology; Osteoprogenitor cells; Recruitment; Rodents; SDF-1 protein; Signal transduction; Signaling; Stem Cell Transplantation; Stem Cells - metabolism; Transcription; Transplantation; Tumors; Vascular endothelial growth factor; Portugal
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018323

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.