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

Victoria Tovar, Helena Cornella, Agrin Moeini, Samuel Vidal, Yujin Hoshida, Daniela Sia, Judit Peix, Laia Cabellos, Clara Alsinet, Sara Torrecilla, Iris Martinez-Quetglas, Juan José Lozano, Christèle Desbois-Mouthon, Manel Solé, Josep Domingo-Domenech, Augusto Villanueva, Josep M. Llovet

Research output: Contribution to journalArticle

47 Citations (Scopus)

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). Conclusions 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.

Original languageEnglish (US)
Pages (from-to)530-540
Number of pages11
JournalGut
Volume66
Issue number3
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

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Neoplastic Stem Cells
Fibroblast Growth Factors
Somatomedins
Hepatocellular Carcinoma
Neoplasms
sorafenib
Inbred NOD Mouse
SCID Mice
Survival
Heterografts
Genes
Disease Progression
Real-Time Polymerase Chain Reaction
Theoretical Models
Stem Cells

Keywords

  • drug resistance
  • Hepatocellular carcinoma
  • molecular genetics
  • molecular mechanisms
  • stem cells

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma. / Tovar, Victoria; Cornella, Helena; Moeini, Agrin; Vidal, Samuel; Hoshida, Yujin; Sia, Daniela; Peix, Judit; Cabellos, Laia; Alsinet, Clara; Torrecilla, Sara; Martinez-Quetglas, Iris; Lozano, Juan José; Desbois-Mouthon, Christèle; Solé, Manel; Domingo-Domenech, Josep; Villanueva, Augusto; Llovet, Josep M.

In: Gut, Vol. 66, No. 3, 01.03.2017, p. 530-540.

Research output: Contribution to journalArticle

Tovar, V, Cornella, H, Moeini, A, Vidal, S, Hoshida, Y, Sia, D, Peix, J, Cabellos, L, Alsinet, C, Torrecilla, S, Martinez-Quetglas, I, Lozano, JJ, Desbois-Mouthon, C, Solé, M, Domingo-Domenech, J, Villanueva, A & Llovet, JM 2017, 'Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma', Gut, vol. 66, no. 3, pp. 530-540. https://doi.org/10.1136/gutjnl-2015-309501
Tovar, Victoria ; Cornella, Helena ; Moeini, Agrin ; Vidal, Samuel ; Hoshida, Yujin ; Sia, Daniela ; Peix, Judit ; Cabellos, Laia ; Alsinet, Clara ; Torrecilla, Sara ; Martinez-Quetglas, Iris ; Lozano, Juan José ; Desbois-Mouthon, Christèle ; Solé, Manel ; Domingo-Domenech, Josep ; Villanueva, Augusto ; Llovet, Josep M. / Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma. In: Gut. 2017 ; Vol. 66, No. 3. pp. 530-540.
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T1 - Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

AU - Tovar, Victoria

AU - Cornella, Helena

AU - Moeini, Agrin

AU - Vidal, Samuel

AU - Hoshida, Yujin

AU - Sia, Daniela

AU - Peix, Judit

AU - Cabellos, Laia

AU - Alsinet, Clara

AU - Torrecilla, Sara

AU - Martinez-Quetglas, Iris

AU - Lozano, Juan José

AU - Desbois-Mouthon, Christèle

AU - Solé, Manel

AU - Domingo-Domenech, Josep

AU - Villanueva, Augusto

AU - Llovet, Josep M.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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). Conclusions 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.

AB - 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). Conclusions 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.

KW - drug resistance

KW - Hepatocellular carcinoma

KW - molecular genetics

KW - molecular mechanisms

KW - stem cells

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