dc.contributor |
Universitat de Barcelona |
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 |
Martinez Quetglas, Iris |
dc.contributor.author |
Lozano Salvatella, Juan José |
dc.contributor.author |
Desbois-Mouthon, Christele |
dc.contributor.author |
Sole, Manel |
dc.contributor.author |
Domingo-Domenech, Josep |
dc.contributor.author |
Villanueva, Augusto |
dc.contributor.author |
Llovet i Bayer, Josep Maria |
dc.date |
2019-02-07T15:02:06Z |
dc.date |
2019-02-07T15:02:06Z |
dc.date |
2017-03-01 |
dc.date |
2019-02-07T15:02:06Z |
dc.identifier.citation |
0017-5749 |
dc.identifier.citation |
677367 |
dc.identifier.uri |
http://hdl.handle.net/2445/128044 |
dc.format |
10 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
BMJ Publishing Group |
dc.relation |
Versió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2015-309501 |
dc.relation |
Gut, 2017, vol. 66, num. 3, p. 530-539 |
dc.relation |
https://doi.org/10.1136/gutjnl-2015-309501 |
dc.rights |
(c) Tovar, Victoria et al., 2017 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Càncer de fetge |
dc.subject |
Medicaments antineoplàstics |
dc.subject |
Liver cancer |
dc.subject |
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.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. |