Endothelial Snail1 in angiogenesis and tumorigenesis

Snail1 is a transcriptional factor with a great relevance in tumor development as it is required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). In this thesis, we reported that tumor endothelial cells did also express Snail1, being key for angiogenesi...

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Autor: Cabrerizo Granados, David
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/670305
Acesso em linha:http://hdl.handle.net/10803/670305
Access Level:acceso abierto
Palavra-chave:Snail1
Angiogénesis
Endothelial cells
Células endoteliales
Breast cancer
Cáncer de mama
576
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oai_identifier_str oai:www.tdx.cat:10803/670305
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Endothelial Snail1 in angiogenesis and tumorigenesis
title Endothelial Snail1 in angiogenesis and tumorigenesis
spellingShingle Endothelial Snail1 in angiogenesis and tumorigenesis
Cabrerizo Granados, David
Snail1
Angiogénesis
Endothelial cells
Células endoteliales
Breast cancer
Cáncer de mama
576
title_short Endothelial Snail1 in angiogenesis and tumorigenesis
title_full Endothelial Snail1 in angiogenesis and tumorigenesis
title_fullStr Endothelial Snail1 in angiogenesis and tumorigenesis
title_full_unstemmed Endothelial Snail1 in angiogenesis and tumorigenesis
title_sort Endothelial Snail1 in angiogenesis and tumorigenesis
dc.creator.none.fl_str_mv Cabrerizo Granados, David
author Cabrerizo Granados, David
author_facet Cabrerizo Granados, David
author_role author
dc.contributor.none.fl_str_mv García de Herreros, Antonio
Peña Arranz, Raúl
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv Snail1
Angiogénesis
Endothelial cells
Células endoteliales
Breast cancer
Cáncer de mama
576
topic Snail1
Angiogénesis
Endothelial cells
Células endoteliales
Breast cancer
Cáncer de mama
576
description Snail1 is a transcriptional factor with a great relevance in tumor development as it is required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). In this thesis, we reported that tumor endothelial cells did also express Snail1, being key for angiogenesis, by promoting endothelial cell migration, invasion and tubulogenesis in vitro. Those roles are associated to Snail1 induction by FGF2 and VEGFA, leading to gene expression profile change in endothelial cells and modulation of their activation status. Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it controls angiogenesis and vessel morphology in Matrigel plug assay. Moreover, endothelium-specific Snail1 depletion in the MMTVPyMT breast cancer murine model delays the initiation of neoplasms, being less advanced and with a papillary morphology, which was corroborated by orthotopic breast tumor inoculation model. These in vivo effects are associated to the inability of Snail1-deficient endothelial cells to promote a full in vitro and in vivo activation of fibroblasts through a reduced FGF2 and CXCL12 signaling; as well as to sustain a complete in vivo angiogenesis, with wider and less invasive neo-vessels. Similar changes on tumor onset and morphology are observed by pretreatment on MMTV-PyMT mice with the angiogenic inhibitor bevacizumab. Checking those results in human breast tumor samples, we could recapitulate most of the findings of our mouse models. Altogether, these findings establish a new role for Snail1 in endothelial cells, not only in angiogenesis but also in tumor onset, development and phenotype
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/670305
url http://hdl.handle.net/10803/670305
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 173 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415342831304704
spelling Endothelial Snail1 in angiogenesis and tumorigenesisCabrerizo Granados, DavidSnail1AngiogénesisEndothelial cellsCélulas endotelialesBreast cancerCáncer de mama576Snail1 is a transcriptional factor with a great relevance in tumor development as it is required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). In this thesis, we reported that tumor endothelial cells did also express Snail1, being key for angiogenesis, by promoting endothelial cell migration, invasion and tubulogenesis in vitro. Those roles are associated to Snail1 induction by FGF2 and VEGFA, leading to gene expression profile change in endothelial cells and modulation of their activation status. Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it controls angiogenesis and vessel morphology in Matrigel plug assay. Moreover, endothelium-specific Snail1 depletion in the MMTVPyMT breast cancer murine model delays the initiation of neoplasms, being less advanced and with a papillary morphology, which was corroborated by orthotopic breast tumor inoculation model. These in vivo effects are associated to the inability of Snail1-deficient endothelial cells to promote a full in vitro and in vivo activation of fibroblasts through a reduced FGF2 and CXCL12 signaling; as well as to sustain a complete in vivo angiogenesis, with wider and less invasive neo-vessels. Similar changes on tumor onset and morphology are observed by pretreatment on MMTV-PyMT mice with the angiogenic inhibitor bevacizumab. Checking those results in human breast tumor samples, we could recapitulate most of the findings of our mouse models. Altogether, these findings establish a new role for Snail1 in endothelial cells, not only in angiogenesis but also in tumor onset, development and phenotypeSnail1 es un factor de transcripción con gran relevancia en el desarrollo tumoral, siendo necesario para la transición epitelio-mesénquima y la activación de fibroblastos asociados al cáncer (CAF). En esta tesis, hemos reportado la expresión de Snail1 en células endoteliales de tumor, jugando un papel fundamental en angiogénesis, promoviendo su migración, invasión y tubulogenesis in vitro. Estas funciones están asociadas a la inducción de Snail1 por FGF2 y VEGF-A, que generan un cambio en el perfil de expresión génica en las células endoteliales y modulan su estado de activación. La depleción específica de Snail1 en el endotelio de ratones adultos no supone un cambio fenotípico evidente; sin embargo, sí controla la angiogénesis y la morfología de los vasos en ensayos de plugs de Matrigel. Además, la eliminación específica de Snail1 en el endotelio del modelo murino de tumores de mama espontáneos MMTV-PyMT provoca el retraso en la iniciación de tumores, siendo éstos menos avanzados y con una morfología papilar. Estos efectos in vivo están asociados a la incapacidad de las células endoteliales sin Snail1 de promover una activación completa de fibroblastos in vitro e in vivo, debido a una señalización reducida de las vías de FGF2 y CXCL12; ni de generar una angiogénesis completa in vivo, con neovasos más anchos y menos invasivos. Cambios similares en la aparición de tumores y en su morfología se observaron en ratones MMTV-PyMT pretratados con el antiangiógenico bevacizumab. En muestras humanas de cáncer de mama pudimos recapitular la mayoría de los descubrimientos de los modelos animales usados. En resumen, estos hallazgos establecen un nuevo papel para Snail1 en las células endoteliales, no solo en angiogénesis, sino también en la aparición tumoral, el desarrollo y el fenotipo del tumor.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraGarcía de Herreros, AntonioPeña Arranz, RaúlUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut202120222020info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion173 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/670305TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6703052026-06-14T12:46:07Z
score 15,301603

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