Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma

Augusto Villanueva, Derek Y. Chiang, Pippa Newell, Judit Peix, Swan Thung, Clara Alsinet, Victoria Tovar, Sasan Roayaie, Beatriz Minguez, Manel Sole, Carlo Battiston, Stijn van Laarhoven, Maria I. Fiel, Analisa Di Feo, Yujin Hoshida, Steven Yea, Sara Toffanin, Alex Ramos, John A. Martignetti, Vincenzo MazzaferroJordi Bruix, Samuel Waxman, Myron Schwartz, Matthew Meyerson, Scott L. Friedman, Josep M. Llovet

Research output: Contribution to journalArticle

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Abstract

Background & Aims: The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. Methods: The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. Results: Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. Conclusions: MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.

Original languageEnglish (US)
Pages (from-to)1972-1983.e11
JournalGastroenterology
Volume135
Issue number6
DOIs
StatePublished - Dec 2008
Externally publishedYes

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Hepatocellular Carcinoma
Epidermal Growth Factor
Heterografts
DNA Copy Number Variations
Mutation
Vascular Endothelial Growth Factor Receptor
Somatomedins
Sirolimus
Liver Neoplasms
Small Interfering RNA
Reverse Transcription
Single Nucleotide Polymorphism
Neoplasms
Cell Survival
Carcinogenesis
Up-Regulation
Down-Regulation
Clinical Trials
Staining and Labeling
Gene Expression

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Villanueva, A., Chiang, D. Y., Newell, P., Peix, J., Thung, S., Alsinet, C., ... Llovet, J. M. (2008). Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma. Gastroenterology, 135(6), 1972-1983.e11. https://doi.org/10.1053/j.gastro.2008.08.008

Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma. / Villanueva, Augusto; Chiang, Derek Y.; Newell, Pippa; Peix, Judit; Thung, Swan; Alsinet, Clara; Tovar, Victoria; Roayaie, Sasan; Minguez, Beatriz; Sole, Manel; Battiston, Carlo; van Laarhoven, Stijn; Fiel, Maria I.; Di Feo, Analisa; Hoshida, Yujin; Yea, Steven; Toffanin, Sara; Ramos, Alex; Martignetti, John A.; Mazzaferro, Vincenzo; Bruix, Jordi; Waxman, Samuel; Schwartz, Myron; Meyerson, Matthew; Friedman, Scott L.; Llovet, Josep M.

In: Gastroenterology, Vol. 135, No. 6, 12.2008, p. 1972-1983.e11.

Research output: Contribution to journalArticle

Villanueva, A, Chiang, DY, Newell, P, Peix, J, Thung, S, Alsinet, C, Tovar, V, Roayaie, S, Minguez, B, Sole, M, Battiston, C, van Laarhoven, S, Fiel, MI, Di Feo, A, Hoshida, Y, Yea, S, Toffanin, S, Ramos, A, Martignetti, JA, Mazzaferro, V, Bruix, J, Waxman, S, Schwartz, M, Meyerson, M, Friedman, SL & Llovet, JM 2008, 'Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma', Gastroenterology, vol. 135, no. 6, pp. 1972-1983.e11. https://doi.org/10.1053/j.gastro.2008.08.008
Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C et al. Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma. Gastroenterology. 2008 Dec;135(6):1972-1983.e11. https://doi.org/10.1053/j.gastro.2008.08.008
Villanueva, Augusto ; Chiang, Derek Y. ; Newell, Pippa ; Peix, Judit ; Thung, Swan ; Alsinet, Clara ; Tovar, Victoria ; Roayaie, Sasan ; Minguez, Beatriz ; Sole, Manel ; Battiston, Carlo ; van Laarhoven, Stijn ; Fiel, Maria I. ; Di Feo, Analisa ; Hoshida, Yujin ; Yea, Steven ; Toffanin, Sara ; Ramos, Alex ; Martignetti, John A. ; Mazzaferro, Vincenzo ; Bruix, Jordi ; Waxman, Samuel ; Schwartz, Myron ; Meyerson, Matthew ; Friedman, Scott L. ; Llovet, Josep M. / Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma. In: Gastroenterology. 2008 ; Vol. 135, No. 6. pp. 1972-1983.e11.
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abstract = "Background & Aims: The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. Methods: The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. Results: Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25{\%} of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. Conclusions: MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.",
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T1 - Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma

AU - Villanueva, Augusto

AU - Chiang, Derek Y.

AU - Newell, Pippa

AU - Peix, Judit

AU - Thung, Swan

AU - Alsinet, Clara

AU - Tovar, Victoria

AU - Roayaie, Sasan

AU - Minguez, Beatriz

AU - Sole, Manel

AU - Battiston, Carlo

AU - van Laarhoven, Stijn

AU - Fiel, Maria I.

AU - Di Feo, Analisa

AU - Hoshida, Yujin

AU - Yea, Steven

AU - Toffanin, Sara

AU - Ramos, Alex

AU - Martignetti, John A.

AU - Mazzaferro, Vincenzo

AU - Bruix, Jordi

AU - Waxman, Samuel

AU - Schwartz, Myron

AU - Meyerson, Matthew

AU - Friedman, Scott L.

AU - Llovet, Josep M.

PY - 2008/12

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N2 - Background & Aims: The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. Methods: The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. Results: Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. Conclusions: MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.

AB - Background & Aims: The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. Methods: The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. Results: Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. Conclusions: MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.

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