March 29, 2017
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Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

Publicated to: GUT. 66 (3): 530-539 - 2017-03-01 66(3), DOI: 10.1136/gutjnl-2015-309501

Authors:

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

CIBERehd, IDIBAPS, Bioinformat Platform, Barcelona, Spain      Hospital Clinic de Barcelona    IDIBAPS    CIBEREHD    CIBER - Centro de Investigacion Biomedica en Red    University of Barcelona - Author
Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA      Icahn School of Medicine at Mount Sinai - Author
Icahn Sch Med Mt Sinai, Div Hematol & Med Oncol, New York, NY 10029 USA      Icahn School of Medicine at Mount Sinai       - Author
Icahn Sch Med Mt Sinai, Liver Canc Program, Div Liver Dis, Dept Med,Tisch Canc Inst, New York, NY 10029 USA      Icahn School of Medicine at Mount Sinai - Author
ICREA, Barcelona, Spain - Author
INSERM, St Antoine Res Ctr, UMR S 938, Paris, France      Sorbonne Universite    Institut National de la Sante et de la Recherche Medicale (Inserm) - Author
Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, Milan, Italy      Fondazione IRCCS Istituto Nazionale Tumori Milan - Author
Univ Barcelona, Canc Translat Res Lab, Hosp Clin, BCLC Grp,IDIBAPS,Liver Unit, Villarroel 170, E-08036 Barcelona, Spain.      IDIBAPS    University of Barcelona    Hospital Clinic de Barcelona - Author
Univ Barcelona, IDIBAPS, Hosp Clin, Dept Pathol, Barcelona, Spain      University of Barcelona    IDIBAPS    Hospital Clinic de Barcelona - Author
Univ Barcelona, Liver Canc Translat Res Lab, Barcelona Clin Liver Canc BCLC Grp, Liver Unit,IDIBAPS,Hosp Clin, Barcelona, Spain      IDIBAPS    Hospital Clinic de Barcelona    University of Barcelona - Author
UPMC Univ Paris 06, Sorbonne Univ, St Antoine Res Ctr, UMR S 938, Paris, France      Sorbonne Universite - Author
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Abstract

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.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.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).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.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Keywords

activationclassificationdrug resistancehepatocellular carcinomainhibitionmolecular geneticsmolecular mechanismsmutationActivationAgedAnimalsAntineoplastic agentsCàncer de fetgeCarcinoma, hepatocellularCell line, tumorClassificationDisease progressionDrug resistanceDrug resistance, neoplasmFemaleFgfr1 protein, humanFibroblast growth factorsGefitinibGene expressionGene expression profilingGrowth-factor receptorHepatocellular carcinomaHumansIgf1r protein, humanInhibitionKinase domainLiver cancerLiver neoplasmsLiver-cancerMaleMedicaments antineoplàsticsMiceMice, inbred balb cMolecular geneticsMolecular mechanismsMutationNiacinamidePhenylurea compoundsReceptor, fibroblast growth factor, type 1Receptor, igf type 1Receptors, somatomedinSignal transductionSomatomedinsSorafenibSpheroids, cellularStem cellsStem-cellsSurvival rateTherapeutic targetsXenograft model antitumor assays

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal GUT due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 3/80, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 5.17. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 3.1 (source consulted: FECYT Mar 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2026-04-27, the following number of citations:

  • WoS: 174
  • Scopus: 94
  • Europe PMC: 119
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-27:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 108.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 109 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 5.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France; Italy; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Tovar Herrador, Victoria Eugenia) and Last Author (Llovet Bayer, Josep M.).

the author responsible for correspondence tasks has been Llovet Bayer, Josep M..

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Awards linked to the item

Bristol-Myers Squibb partially supported the study with a research grant. JML is supported by grants from The European Commission Framework Programme 7 (HEP-CAR grant, Number 667273-2 and HEPTROMIC, Proposal No: 259744), the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF-2013-41027), and the Asociacion Espanola Contra el Cancer (AECC). Victoria Tovar is supported by a grant from the AECC. Helena Cornella and Clara Alsinet are recipients of grants from the Instituto de Salud Carlos III (PFIS programme). Agrin Moeini is recipient of a grant from Spanish National Health Institute (FPI programme). Daniela Sia is supported by the Italian Association for Cancer Research and the Italian National Ministry of Health. Yujin Hoshida is supported by grants from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099558). Christele Desbois-Mouthon is supported by French institute of health and medical research (INSERM) and French Institute of Cancer (INCA, grant No: INCa-DGOS_5790).
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