title: Akt and mTORC1 have different roles during liver tumorigenesis in mice.
abstract: OBJECTIVE
  Phosphatidylinositide 3-kinase (PI3K) is deregulated in many human tumor types, including primary liver malignancies. The kinase v-akt murine thymoma viral oncogene homolog 1 (Akt) and mammalian target of rapamycin complex (mTORC1) are effectors of PI3K that promote cell growth and survival, but their individual roles in tumorigenesis are not well defined.
  
  
  METHODS
  In livers of albumin (Alb)-Cre mice, we selectively deleted tuberous sclerosis (Tsc)1, a negative regulator of Ras homolog enriched in brain and mTORC1, along with Phosphatase and tensin homolog (Pten), a negative regulator of PI3K. Tumor tissues were characterized by histologic and biochemical analyses.
  
  
  RESULTS
  The Tsc1fl/fl;AlbCre, Ptenfl/fl;AlbCre, and Tsc1fl/fl;Ptenfl/fl;AlbCre mice developed liver tumors that differed in size, number, and histologic features. Livers of Tsc1fl/fl;AlbCre mice did not develop steatosis; tumors arose later than in the other strains of mice and were predominantly hepatocellular carcinomas. Livers of the Ptenfl/fl;AlbCre mice developed steatosis and most of the tumors that formed were intrahepatic cholangiocarcinomas. Livers of Tsc1fl/fl;Ptenfl/fl;AlbCre formed large numbers of tumors, of mixed histologies, with the earliest onset of any strain, indicating that loss of Tsc1 and Pten have synergistic effects on tumorigenesis. In these mice, the combination of rapamycin and MK2206 was more effective in reducing liver cell proliferation and inducing cell death than either reagent alone. Tumor differentiation correlated with Akt and mTORC1 activities; the ratio of Akt:mTORC1 activity was high throughout the course of intrahepatic cholangiocarcinomas development and low during hepatocellular carcinoma development. Compared with surrounding nontumor liver tissue, tumors from all 3 strains had increased activities of Akt, mTORC1, and mitogen-activated protein kinase and overexpressed fibroblast growth factor receptor 1. Inhibition of fibroblast growth factor receptor 1 in Tsc1-null mice suppressed Akt and mitogen-activated protein kinase activities in tumor cells.
  
  
  CONCLUSIONS
  Based on analyses of knockout mice, mTORC1 and Akt have different yet synergistic effects during the development of liver tumors in mice.
authors: Department of Surgery, University of Washington, Seattle, WA 98195, USA.
authors: Heidi L
authors: HL
authors: Kenerson
authors: Matthew M
authors: MM
authors: Yeh
authors: Machiko
authors: M
authors: Kazami
authors: Xiuyun
authors: X
authors: Jiang
authors: Kimberly J
authors: KJ
authors: Riehle
authors: Rebecca L
authors: RL
authors: McIntyre
authors: James O
authors: JO
authors: Park
authors: Steve
authors: S
authors: Kwon
authors: Jean S
authors: JS
authors: Campbell
authors: Raymond S
authors: RS
authors: Yeung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D046912:Multiprotein Complexes; D012334:RNA, Neoplasm; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
references: PLoS One. 2011 Mar 29;6(3):e18075
references: 21479224
references: Sci Signal. 2012 Mar 27;5(217):ra24
references: 22457330
references: J Clin Invest. 2008 Sep;118(9):3065-74
references: 18725988
references: Dig Liver Dis. 2010 Jul;42 Suppl 3:S206-14
references: 20547305
references: Science. 2011 Jun 10;332(6035):1317-22
references: 21659604
references: Am J Pathol. 2004 Jun;164(6):2229-40
references: 15161655
references: Gastroenterology. 2011 Mar;140(3):1071-83
references: 21147110
references: Cancer Res. 2006 Feb 1;66(3):1481-90
references: 16452204
references: Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35
references: 21157483
references: Gastroenterology. 2010 Dec;139(6):2170-82
references: 20837017
references: J Clin Invest. 2006 Jul;116(7):1843-52
references: 16767220
references: Liver Int. 2009 Mar;29(3):399-405
references: 18492014
references: Gastroenterology. 2008 Dec;135(6):1972-83, 1983.e1-11
references: 18929564
references: J Gastroenterol Hepatol. 2010 Sep;25(9):1485-92
references: 20796144
references: Stem Cell Rev. 2005;1(3):253-60
references: 17142862
references: Clin Cancer Res. 2012 Apr 1;18(7):2090-8
references: 22238246
references: Nat Genet. 2011 Jan;43(1):34-41
references: 21113154
references: Cancer. 2011 Nov 15;117(22):5094-102
references: 21538343
references: Clin Cancer Res. 2004 Dec 15;10(24):8421-5
references: 15623621
references: Cancer Res. 2010 Jan 1;70(1):288-98
references: 20028854
references: J Cell Biol. 2004 Jul 19;166(2):213-23
references: 15249583
references: Hepatology. 2008 May;47(5):1702-13
references: 18398918
references: Dig Liver Dis. 2010 Jul;42 Suppl 3:S235-41
references: 20547309
references: Cell. 1997 May 30;89(5):693-702
references: 9182757
references: Nat Genet. 2011 May;43(5):464-9
references: 21499249
references: Gastroenterology. 2007 Aug;133(2):647-58
references: 17681183
references: Hum Pathol. 2012 May;43(5):737-46
references: 22018903