title: Bone marrow-derived endothelial progenitors expressing Delta-like 4 (Dll4) regulate tumor angiogenesis.
abstract: 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.
authors.affiliation: Angiogenesis Laboratory, CIPM/Portuguese Institute of Oncology, Lisbon, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Real
authors.forename: Leonor
authors.initials: L
authors.lastname: Remédio
authors.forename: Francisco
authors.initials: F
authors.lastname: Caiado
authors.forename: Cátia
authors.initials: C
authors.lastname: Igreja
authors.forename: Cristina
authors.initials: C
authors.lastname: Borges
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.forename: Perpétua
authors.initials: P
authors.lastname: Pinto-do-Ó
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Antonio
authors.initials: A
authors.lastname: Duarte
authors.forename: Sérgio
authors.initials: S
authors.lastname: Dias
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology*; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins