Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients

Background: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common...

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Autores: Gabasa Ferràndez, Marta, Ikemori, Rafael, Hilberg, F., Reguart, Noemí, Alcaraz Casademunt, Jordi
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/124571
Acesso em linha:https://hdl.handle.net/2445/124571
Access Level:acceso abierto
Palavra-chave:Fibroblasts
Fibrosi pulmonar
Reacció en cadena de la polimerasa
Farmacologia
Càncer de pulmó
Pulmonary fibrosis
Polymerase chain reaction
Pharmacology
Lung cancer
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spelling Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patientsGabasa Ferràndez, MartaIkemori, RafaelHilberg, F.Reguart, NoemíAlcaraz Casademunt, JordiFibroblastsFibrosi pulmonarReacció en cadena de la polimerasaFarmacologiaCàncer de pulmóFibroblastsPulmonary fibrosisPolymerase chain reactionPharmacologyLung cancerBackground: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods: We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta 1, which is upregulated in lung cancer.Results: Nintedanib dose-dependently inhibited the TGF-beta 1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours.Cancer Research UK2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/124571Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/bjc.2017.270British Journal of Cancer, 2017, vol. 117, num. 8, p. 1128-1138https://doi.org/10.1038/bjc.2017.270cc-by-nc-sa (c) Gabasa Ferràndez, Marta et al., 2017http://creativecommons.org/licenses/by-nc-sa/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1245712026-05-27T06:46:51Z
dc.title.none.fl_str_mv Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
title Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
spellingShingle Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
Gabasa Ferràndez, Marta
Fibroblasts
Fibrosi pulmonar
Reacció en cadena de la polimerasa
Farmacologia
Càncer de pulmó
Fibroblasts
Pulmonary fibrosis
Polymerase chain reaction
Pharmacology
Lung cancer
title_short Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
title_full Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
title_fullStr Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
title_full_unstemmed Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
title_sort Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
dc.creator.none.fl_str_mv Gabasa Ferràndez, Marta
Ikemori, Rafael
Hilberg, F.
Reguart, Noemí
Alcaraz Casademunt, Jordi
author Gabasa Ferràndez, Marta
author_facet Gabasa Ferràndez, Marta
Ikemori, Rafael
Hilberg, F.
Reguart, Noemí
Alcaraz Casademunt, Jordi
author_role author
author2 Ikemori, Rafael
Hilberg, F.
Reguart, Noemí
Alcaraz Casademunt, Jordi
author2_role author
author
author
author
dc.subject.none.fl_str_mv Fibroblasts
Fibrosi pulmonar
Reacció en cadena de la polimerasa
Farmacologia
Càncer de pulmó
Fibroblasts
Pulmonary fibrosis
Polymerase chain reaction
Pharmacology
Lung cancer
topic Fibroblasts
Fibrosi pulmonar
Reacció en cadena de la polimerasa
Farmacologia
Càncer de pulmó
Fibroblasts
Pulmonary fibrosis
Polymerase chain reaction
Pharmacology
Lung cancer
description Background: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods: We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta 1, which is upregulated in lung cancer.Results: Nintedanib dose-dependently inhibited the TGF-beta 1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/124571
url https://hdl.handle.net/2445/124571
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/bjc.2017.270
British Journal of Cancer, 2017, vol. 117, num. 8, p. 1128-1138
https://doi.org/10.1038/bjc.2017.270
dc.rights.none.fl_str_mv cc-by-nc-sa (c) Gabasa Ferràndez, Marta et al., 2017
http://creativecommons.org/licenses/by-nc-sa/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-sa (c) Gabasa Ferràndez, Marta et al., 2017
http://creativecommons.org/licenses/by-nc-sa/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cancer Research UK
publisher.none.fl_str_mv Cancer Research UK
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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