MET is required for the recruitment of anti-tumoural neutrophils
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/41056 |
Resumo: | Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-a or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases. |
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MET is required for the recruitment of anti-tumoural neutrophilsCiências Médicas::Medicina BásicaScience & TechnologyMutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-a or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.The authors thank: R. Stirparo, M. Mambretti and Y. Jonsson for technical assistance; G. Serini, L. Trusolino and P. Bruhns for comments; and E. Radaelli for valuable advice on histological analyses. V.F. and G.D.C. were supported by grants from the Fonds Wetenschappelijk Onderzoek (FWO), A.C. by the Fondazione Umberto Veronesi. S.W. is supported by a Wellcome Trust Senior Clinical Fellowship Award. M. M. is supported by a European Research Council starting grant.Nature Publishing Group[et al.]Universidade do MinhoFinisguerra, VeronicaConza, Giusy DiMatteo, Mario DiSerneels, JensCosta, Sandra Maria Araújo daThompson, A. A. RogerWauters, ElsWalmsley, SarahPrenen, HansGranot, Zvi2015-062015-06-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/41056engFinisguerra, V., Di Conza, G., Di Matteo, M., Serneels, J., Costa, S., et. al. (2015). MET is required for the recruitment of anti-tumoural neutrophils. Nature0028-083610.1038/nature1440725985180http://www.nature.com/nature/journal/v522/n7556/full/nature14407.htmlinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T11:54:36Zoai:repositorium.sdum.uminho.pt:1822/41056Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:44:05.044923Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
MET is required for the recruitment of anti-tumoural neutrophils |
title |
MET is required for the recruitment of anti-tumoural neutrophils |
spellingShingle |
MET is required for the recruitment of anti-tumoural neutrophils Finisguerra, Veronica Ciências Médicas::Medicina Básica Science & Technology |
title_short |
MET is required for the recruitment of anti-tumoural neutrophils |
title_full |
MET is required for the recruitment of anti-tumoural neutrophils |
title_fullStr |
MET is required for the recruitment of anti-tumoural neutrophils |
title_full_unstemmed |
MET is required for the recruitment of anti-tumoural neutrophils |
title_sort |
MET is required for the recruitment of anti-tumoural neutrophils |
author |
Finisguerra, Veronica |
author_facet |
Finisguerra, Veronica Conza, Giusy Di Matteo, Mario Di Serneels, Jens Costa, Sandra Maria Araújo da Thompson, A. A. Roger Wauters, Els Walmsley, Sarah Prenen, Hans Granot, Zvi |
author_role |
author |
author2 |
Conza, Giusy Di Matteo, Mario Di Serneels, Jens Costa, Sandra Maria Araújo da Thompson, A. A. Roger Wauters, Els Walmsley, Sarah Prenen, Hans Granot, Zvi |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
[et al.] Universidade do Minho |
dc.contributor.author.fl_str_mv |
Finisguerra, Veronica Conza, Giusy Di Matteo, Mario Di Serneels, Jens Costa, Sandra Maria Araújo da Thompson, A. A. Roger Wauters, Els Walmsley, Sarah Prenen, Hans Granot, Zvi |
dc.subject.por.fl_str_mv |
Ciências Médicas::Medicina Básica Science & Technology |
topic |
Ciências Médicas::Medicina Básica Science & Technology |
description |
Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-a or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases. |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015-06 2015-06-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/41056 |
url |
http://hdl.handle.net/1822/41056 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Finisguerra, V., Di Conza, G., Di Matteo, M., Serneels, J., Costa, S., et. al. (2015). MET is required for the recruitment of anti-tumoural neutrophils. Nature 0028-0836 10.1038/nature14407 25985180 http://www.nature.com/nature/journal/v522/n7556/full/nature14407.html |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Nature Publishing Group |
publisher.none.fl_str_mv |
Nature Publishing Group |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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