title: Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions.
abstract: Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy.
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.
authors.forename: Ana-Rita
authors.initials: AR
authors.lastname: Pedrosa
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Carvalho
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Graça
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Peleteiro
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Muenster, Germany.|Faculty of Medicine, University of Muenster, Muenster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), University of Lisbon, Lisbon, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Duarte
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018827:Carcinoma, Lewis Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D000860:Hypoxia; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010477:Perfusion; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins
keywords: Jagged1; Notch; TRAMP; angiocrine; tumor angiogenesis