Cargando…
Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions
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 th...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695194/ https://www.ncbi.nlm.nih.gov/pubmed/26213336 |
_version_ | 1782407618287894528 |
---|---|
author | Pedrosa, Ana-Rita Trindade, Alexandre Carvalho, Catarina Graça, José Carvalho, Sandra Peleteiro, Maria C. Adams, Ralf H. Duarte, António |
author_facet | Pedrosa, Ana-Rita Trindade, Alexandre Carvalho, Catarina Graça, José Carvalho, Sandra Peleteiro, Maria C. Adams, Ralf H. Duarte, António |
author_sort | Pedrosa, Ana-Rita |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4695194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-46951942016-01-26 Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions Pedrosa, Ana-Rita Trindade, Alexandre Carvalho, Catarina Graça, José Carvalho, Sandra Peleteiro, Maria C. Adams, Ralf H. Duarte, António Oncotarget Research Paper 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. Impact Journals LLC 2015-06-08 /pmc/articles/PMC4695194/ /pubmed/26213336 Text en Copyright: © 2015 Pedrosa et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Pedrosa, Ana-Rita Trindade, Alexandre Carvalho, Catarina Graça, José Carvalho, Sandra Peleteiro, Maria C. Adams, Ralf H. Duarte, António Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
title | Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
title_full | Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
title_fullStr | Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
title_full_unstemmed | Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
title_short | Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
title_sort | endothelial jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695194/ https://www.ncbi.nlm.nih.gov/pubmed/26213336 |
work_keys_str_mv | AT pedrosaanarita endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT trindadealexandre endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT carvalhocatarina endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT gracajose endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT carvalhosandra endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT peleteiromariac endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT adamsralfh endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions AT duarteantonio endothelialjagged1promotessolidtumorgrowththroughbothproangiogenicandangiocrinefunctions |