Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

Objective: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sor...

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Autores: Tovar, Victoria, Cornella, Helena, Moeini, Agrin, Vidal, Samuel, Hoshida, Yujin, Sia, Daniela, Peix, Judit, Cabellos, Laia, Alsinet, Clara, Torrecilla, Sara, Martínez Quetglas, Iris, Lozano Salvatella, Juan José, Desbois-Mouthon, Christele, Sole, Manel, Domingo Domènech, Josep Maria, Villanueva, Augusto, Llovet i Bayer, Josep Maria
Tipo de documento: artigo
Estado:Versión aceptada para publicación
Data de publicação:2017
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/128044
Acesso em linha:https://hdl.handle.net/2445/128044
Access Level:Acceso aberto
Palavra-chave:Càncer de fetge
Medicaments antineoplàstics
Liver cancer
Antineoplastic agents
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spelling Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinomaTovar, VictoriaCornella, HelenaMoeini, AgrinVidal, SamuelHoshida, YujinSia, DanielaPeix, JuditCabellos, LaiaAlsinet, ClaraTorrecilla, SaraMartínez Quetglas, IrisLozano Salvatella, Juan JoséDesbois-Mouthon, ChristeleSole, ManelDomingo Domènech, Josep MariaVillanueva, AugustoLlovet i Bayer, Josep MariaCàncer de fetgeMedicaments antineoplàsticsLiver cancerAntineoplastic agentsObjective: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance. Design: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts. Results: Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC). Conclusion: Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.BMJ Publishing Group2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/128044Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2015-309501Gut, 2017, vol. 66, num. 3, p. 530-539https://doi.org/10.1136/gutjnl-2015-309501info:eu-repo/grantAgreement/EC/H2020/667273(c) Tovar, Victoria et al., 2017info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1280442026-05-27T06:46:51Z
dc.title.none.fl_str_mv Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
title Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
spellingShingle Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
Tovar, Victoria
Càncer de fetge
Medicaments antineoplàstics
Liver cancer
Antineoplastic agents
title_short Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
title_full Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
title_fullStr Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
title_full_unstemmed Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
title_sort Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
dc.creator.none.fl_str_mv Tovar, Victoria
Cornella, Helena
Moeini, Agrin
Vidal, Samuel
Hoshida, Yujin
Sia, Daniela
Peix, Judit
Cabellos, Laia
Alsinet, Clara
Torrecilla, Sara
Martínez Quetglas, Iris
Lozano Salvatella, Juan José
Desbois-Mouthon, Christele
Sole, Manel
Domingo Domènech, Josep Maria
Villanueva, Augusto
Llovet i Bayer, Josep Maria
author Tovar, Victoria
author_facet Tovar, Victoria
Cornella, Helena
Moeini, Agrin
Vidal, Samuel
Hoshida, Yujin
Sia, Daniela
Peix, Judit
Cabellos, Laia
Alsinet, Clara
Torrecilla, Sara
Martínez Quetglas, Iris
Lozano Salvatella, Juan José
Desbois-Mouthon, Christele
Sole, Manel
Domingo Domènech, Josep Maria
Villanueva, Augusto
Llovet i Bayer, Josep Maria
author_role author
author2 Cornella, Helena
Moeini, Agrin
Vidal, Samuel
Hoshida, Yujin
Sia, Daniela
Peix, Judit
Cabellos, Laia
Alsinet, Clara
Torrecilla, Sara
Martínez Quetglas, Iris
Lozano Salvatella, Juan José
Desbois-Mouthon, Christele
Sole, Manel
Domingo Domènech, Josep Maria
Villanueva, Augusto
Llovet i Bayer, Josep Maria
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de fetge
Medicaments antineoplàstics
Liver cancer
Antineoplastic agents
topic Càncer de fetge
Medicaments antineoplàstics
Liver cancer
Antineoplastic agents
description Objective: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance. Design: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts. Results: Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC). Conclusion: Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/128044
url https://hdl.handle.net/2445/128044
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2015-309501
Gut, 2017, vol. 66, num. 3, p. 530-539
https://doi.org/10.1136/gutjnl-2015-309501
info:eu-repo/grantAgreement/EC/H2020/667273
dc.rights.none.fl_str_mv (c) Tovar, Victoria et al., 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Tovar, Victoria et al., 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
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 15,300719

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