Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2

Vivian A. Galicia, Lina He, Hien Dang, Gary Kanel, Christopher Vendryes, Barbara A. French, Ni Zeng, Jenniferann Bayan, Wei Ding, Kasper S. Wang, Samuel French, Morris J. Birnbaum, C. Bart Rountree, Bangyan L. Stiles

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Background & Aims The tumor suppressor PTEN inhibits AKT2 signaling; both are aberrantly expressed in liver tumors. We investigated how PTEN and AKT2 regulate liver carcinogenesis. Loss of PTEN leads to spontaneous development of liver tumors from progenitor cells. We investigated how the loss of PTEN activates liver progenitor cells and induces tumorigenesis. Methods We studied mice with liver-specific disruptions in Pten and the combination of Pten and Akt2 to investigate mechanisms of liver carcinogenesis. Results PTEN loss leads to hepatic injury and establishes selective pressure for tumor-initiating cells (TICs), which proliferate to form mixed-lineage tumors. The Pten-null mice had increasing levels of hepatic injury before proliferation of hepatic progenitors. Attenuation of hepatic injury by deletion of Akt2 reduced progenitor cell proliferation and delayed tumor development. In Pten/Akt2-null mice given 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC), we found that the primary effect of AKT2 loss was attenuation of hepatic injury and not inhibition of progenitor-cell proliferation in response to injury. Conclusions Liver carcinogenesis in Pten-null mice requires not only the transformation of TICs but selection pressure from hepatic injury and cell death, which activates TICs. Further research is required to elucidate the mechanism for hepatic injury and its relationship with TIC activation.

Original languageEnglish (US)
Pages (from-to)2170-2182
Number of pages13
JournalGastroenterology
Volume139
Issue number6
DOIs
StatePublished - Dec 2010

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Stem Cells
Liver
Wounds and Injuries
Neoplasms
Neoplastic Stem Cells
Carcinogenesis
Cell Proliferation
Hepatocytes
Cell Death
Pressure

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Galicia, V. A., He, L., Dang, H., Kanel, G., Vendryes, C., French, B. A., ... Stiles, B. L. (2010). Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology, 139(6), 2170-2182. https://doi.org/10.1053/j.gastro.2010.09.002
Galicia, Vivian A. ; He, Lina ; Dang, Hien ; Kanel, Gary ; Vendryes, Christopher ; French, Barbara A. ; Zeng, Ni ; Bayan, Jenniferann ; Ding, Wei ; Wang, Kasper S. ; French, Samuel ; Birnbaum, Morris J. ; Rountree, C. Bart ; Stiles, Bangyan L. / Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2. In: Gastroenterology. 2010 ; Vol. 139, No. 6. pp. 2170-2182.
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title = "Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2",
abstract = "Background & Aims The tumor suppressor PTEN inhibits AKT2 signaling; both are aberrantly expressed in liver tumors. We investigated how PTEN and AKT2 regulate liver carcinogenesis. Loss of PTEN leads to spontaneous development of liver tumors from progenitor cells. We investigated how the loss of PTEN activates liver progenitor cells and induces tumorigenesis. Methods We studied mice with liver-specific disruptions in Pten and the combination of Pten and Akt2 to investigate mechanisms of liver carcinogenesis. Results PTEN loss leads to hepatic injury and establishes selective pressure for tumor-initiating cells (TICs), which proliferate to form mixed-lineage tumors. The Pten-null mice had increasing levels of hepatic injury before proliferation of hepatic progenitors. Attenuation of hepatic injury by deletion of Akt2 reduced progenitor cell proliferation and delayed tumor development. In Pten/Akt2-null mice given 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC), we found that the primary effect of AKT2 loss was attenuation of hepatic injury and not inhibition of progenitor-cell proliferation in response to injury. Conclusions Liver carcinogenesis in Pten-null mice requires not only the transformation of TICs but selection pressure from hepatic injury and cell death, which activates TICs. Further research is required to elucidate the mechanism for hepatic injury and its relationship with TIC activation.",
author = "Galicia, {Vivian A.} and Lina He and Hien Dang and Gary Kanel and Christopher Vendryes and French, {Barbara A.} and Ni Zeng and Jenniferann Bayan and Wei Ding and Wang, {Kasper S.} and Samuel French and Birnbaum, {Morris J.} and Rountree, {C. Bart} and Stiles, {Bangyan L.}",
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Galicia, VA, He, L, Dang, H, Kanel, G, Vendryes, C, French, BA, Zeng, N, Bayan, J, Ding, W, Wang, KS, French, S, Birnbaum, MJ, Rountree, CB & Stiles, BL 2010, 'Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2', Gastroenterology, vol. 139, no. 6, pp. 2170-2182. https://doi.org/10.1053/j.gastro.2010.09.002

Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2. / Galicia, Vivian A.; He, Lina; Dang, Hien; Kanel, Gary; Vendryes, Christopher; French, Barbara A.; Zeng, Ni; Bayan, Jenniferann; Ding, Wei; Wang, Kasper S.; French, Samuel; Birnbaum, Morris J.; Rountree, C. Bart; Stiles, Bangyan L.

In: Gastroenterology, Vol. 139, No. 6, 12.2010, p. 2170-2182.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Expansion of hepatic tumor progenitor cells in pten-null mice requires liver injury and is reversed by loss of AKT2

AU - Galicia, Vivian A.

AU - He, Lina

AU - Dang, Hien

AU - Kanel, Gary

AU - Vendryes, Christopher

AU - French, Barbara A.

AU - Zeng, Ni

AU - Bayan, Jenniferann

AU - Ding, Wei

AU - Wang, Kasper S.

AU - French, Samuel

AU - Birnbaum, Morris J.

AU - Rountree, C. Bart

AU - Stiles, Bangyan L.

PY - 2010/12

Y1 - 2010/12

N2 - Background & Aims The tumor suppressor PTEN inhibits AKT2 signaling; both are aberrantly expressed in liver tumors. We investigated how PTEN and AKT2 regulate liver carcinogenesis. Loss of PTEN leads to spontaneous development of liver tumors from progenitor cells. We investigated how the loss of PTEN activates liver progenitor cells and induces tumorigenesis. Methods We studied mice with liver-specific disruptions in Pten and the combination of Pten and Akt2 to investigate mechanisms of liver carcinogenesis. Results PTEN loss leads to hepatic injury and establishes selective pressure for tumor-initiating cells (TICs), which proliferate to form mixed-lineage tumors. The Pten-null mice had increasing levels of hepatic injury before proliferation of hepatic progenitors. Attenuation of hepatic injury by deletion of Akt2 reduced progenitor cell proliferation and delayed tumor development. In Pten/Akt2-null mice given 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC), we found that the primary effect of AKT2 loss was attenuation of hepatic injury and not inhibition of progenitor-cell proliferation in response to injury. Conclusions Liver carcinogenesis in Pten-null mice requires not only the transformation of TICs but selection pressure from hepatic injury and cell death, which activates TICs. Further research is required to elucidate the mechanism for hepatic injury and its relationship with TIC activation.

AB - Background & Aims The tumor suppressor PTEN inhibits AKT2 signaling; both are aberrantly expressed in liver tumors. We investigated how PTEN and AKT2 regulate liver carcinogenesis. Loss of PTEN leads to spontaneous development of liver tumors from progenitor cells. We investigated how the loss of PTEN activates liver progenitor cells and induces tumorigenesis. Methods We studied mice with liver-specific disruptions in Pten and the combination of Pten and Akt2 to investigate mechanisms of liver carcinogenesis. Results PTEN loss leads to hepatic injury and establishes selective pressure for tumor-initiating cells (TICs), which proliferate to form mixed-lineage tumors. The Pten-null mice had increasing levels of hepatic injury before proliferation of hepatic progenitors. Attenuation of hepatic injury by deletion of Akt2 reduced progenitor cell proliferation and delayed tumor development. In Pten/Akt2-null mice given 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC), we found that the primary effect of AKT2 loss was attenuation of hepatic injury and not inhibition of progenitor-cell proliferation in response to injury. Conclusions Liver carcinogenesis in Pten-null mice requires not only the transformation of TICs but selection pressure from hepatic injury and cell death, which activates TICs. Further research is required to elucidate the mechanism for hepatic injury and its relationship with TIC activation.

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U2 - 10.1053/j.gastro.2010.09.002

DO - 10.1053/j.gastro.2010.09.002

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