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Akt and mTORC1 have different roles during liver tumorigenesis in mice

Heidi L Kenerson1, Matthew M Yeh, Machiko Kazami

  • 1Department of Surgery, University of Washington, Seattle, WA 98195, USA.

Gastroenterology
|February 5, 2013
PubMed
Abstract

Insights

Loss of Tsc1 and Pten synergistically promotes liver tumorigenesis in mice. Targeting both mTORC1 (mammalian target of rapamycin complex 1) and Akt pathways simultaneously offers a promising therapeutic strategy for liver cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Phosphatidylinositide 3-kinase (PI3K) pathway is frequently dysregulated in human cancers, including primary liver malignancies.
  • Key effectors of PI3K, v-akt murine thymoma viral oncogene homolog 1 (Akt) and mammalian target of rapamycin complex 1 (mTORC1), are crucial for cell growth and survival.
  • The distinct roles of Akt and mTORC1 in liver tumorigenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the individual and combined roles of tuberous sclerosis 1 (Tsc1) and Phosphatase and tensin homolog (Pten) in liver tumor development.
  • To elucidate the downstream signaling events involving Akt and mTORC1 in different types of liver tumors.
  • To evaluate the efficacy of combined therapeutic inhibition of Akt and mTORC1 signaling in preclinical models.

Main Methods:

  • Generation of genetically engineered mouse models with selective deletion of Tsc1 and/or Pten in liver cells using Alb-Cre technology.
  • Histological and biochemical characterization of liver tumors developed in knockout mice.
  • Pharmacological inhibition of Akt and mTORC1 pathways using rapamycin and MK2206, and assessment of fibroblast growth factor receptor 1 (FGFR1) signaling.

Main Results:

  • Conditional deletion of Tsc1 and/or Pten in mouse livers resulted in distinct liver tumor types, sizes, and onset.
  • Loss of Tsc1 and Pten exhibited synergistic effects on liver tumorigenesis, leading to earlier tumor onset and mixed histologies.
  • Combined inhibition of Akt and mTORC1 pathways with rapamycin and MK2206 demonstrated superior efficacy in reducing tumor cell proliferation and inducing apoptosis compared to single-agent treatment.
  • Tumor differentiation correlated with Akt and mTORC1 activity levels, with specific ratios associated with hepatocellular carcinoma versus intrahepatic cholangiocarcinoma development.
  • Increased activity of Akt, mTORC1, and mitogen-activated protein kinase (MAPK), along with FGFR1 overexpression, was observed in tumors across all genetic models.

Conclusions:

  • Tsc1 and Pten loss cooperatively drive liver tumorigenesis through synergistic activation of downstream signaling pathways.
  • Akt and mTORC1 play distinct yet interconnected roles in the initiation and progression of different liver tumor subtypes.
  • Targeting both Akt and mTORC1, potentially in combination with FGFR1 inhibition, represents a viable therapeutic strategy for liver malignancies driven by PI3K pathway activation.

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