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http://hdl.handle.net/2445/128044
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DC Field | Value | Language |
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dc.contributor.author | Tovar, Victoria | - |
dc.contributor.author | Cornella, Helena | - |
dc.contributor.author | Moeini, Agrin | - |
dc.contributor.author | Vidal, Samuel | - |
dc.contributor.author | Hoshida, Yujin | - |
dc.contributor.author | Sia, Daniela | - |
dc.contributor.author | Peix, Judit | - |
dc.contributor.author | Cabellos, Laia | - |
dc.contributor.author | Alsinet, Clara | - |
dc.contributor.author | Torrecilla, Sara | - |
dc.contributor.author | Martínez Quetglas, Iris | - |
dc.contributor.author | Lozano Salvatella, Juan José | - |
dc.contributor.author | Desbois-Mouthon, Christele | - |
dc.contributor.author | Sole, Manel | - |
dc.contributor.author | Domingo Domènech, Josep Maria | - |
dc.contributor.author | Villanueva, Augusto | - |
dc.contributor.author | Llovet i Bayer, Josep Maria | - |
dc.date.accessioned | 2019-02-07T15:02:06Z | - |
dc.date.available | 2019-02-07T15:02:06Z | - |
dc.date.issued | 2017-03-01 | - |
dc.identifier.issn | 0017-5749 | - |
dc.identifier.uri | http://hdl.handle.net/2445/128044 | - |
dc.description.abstract | 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. | - |
dc.format.extent | 10 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | BMJ Publishing Group | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2015-309501 | - |
dc.relation.ispartof | Gut, 2017, vol. 66, num. 3, p. 530-539 | - |
dc.relation.uri | https://doi.org/10.1136/gutjnl-2015-309501 | - |
dc.rights | (c) Tovar, Victoria et al., 2017 | - |
dc.source | Articles publicats en revistes (Medicina) | - |
dc.subject.classification | Càncer de fetge | - |
dc.subject.classification | Medicaments antineoplàstics | - |
dc.subject.other | Liver cancer | - |
dc.subject.other | Antineoplastic agents | - |
dc.title | Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 677367 | - |
dc.date.updated | 2019-02-07T15:02:06Z | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/667273/EU//HEP-CAR | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 26658144 | - |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Medicina) |
Files in This Item:
File | Description | Size | Format | |
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677367.pdf | 2.31 MB | Adobe PDF | View/Open |
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