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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Autophagy-deficient mice develop multiple liver tumors
Akito Takamura1, Masaaki Komatsu, Taichi Hara
1Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Abstract:
Autophagy is a major pathway for degradation of cytoplasmic proteins and organelles, and has been implicated in tumor suppression. Here, we report that mice with systemic mosaic deletion of Atg5 and liver-specific Atg7⁻/⁻ mice develop benign liver adenomas. These tumor cells originate autophagy-deficient hepatocytes and show mitochondrial swelling, p62 accumulation, and oxidative stress and genomic damage responses. The size of the Atg7⁻/⁻ liver tumors is reduced by simultaneous deletion of p62. These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression.
Insights
Autophagy, a cellular degradation process, prevents liver tumor formation in mice. Blocking autophagy leads to liver adenomas, and p62 accumulation worsens tumor growth, highlighting autophagy
Area of Science:
- Cellular Biology
- Oncology
- Molecular Biology
Background:
- Autophagy is a fundamental cellular process responsible for degrading damaged proteins and organelles.
- Autophagy plays a crucial role in maintaining cellular homeostasis and has been linked to tumor suppression.
- Dysregulation of autophagy is increasingly recognized in various pathologies, including cancer.
Purpose of the Study:
- To investigate the role of autophagy in the suppression of spontaneous liver tumorigenesis.
- To elucidate the cellular mechanisms by which autophagy deficiency contributes to tumor development.
- To assess the impact of p62, a key autophagy substrate, on tumor progression in the absence of autophagy.
Main Methods:
- Generated mice with systemic mosaic deletion of Atg5 (autophagy-related gene 5).
- Created liver-specific Atg7 knockout (Atg7⁻/⁻) mice to study liver tumorigenesis.
- Analyzed tumor characteristics, including mitochondrial morphology, p62 levels, oxidative stress, and genomic damage.
Main Results:
- Mice with Atg5 deletion and liver-specific Atg7 deficiency developed benign liver adenomas.
- Tumor cells exhibited hallmarks of autophagy deficiency: mitochondrial swelling, p62 accumulation, and increased oxidative stress and genomic damage.
- Simultaneous deletion of p62 significantly reduced the size of Atg7⁻/⁻ liver tumors, indicating p62's role in tumor progression.
Conclusions:
- Autophagy is essential for the cell-intrinsic suppression of spontaneous tumorigenesis, particularly in the liver.
- Autophagy deficiency in hepatocytes leads to mitochondrial dysfunction, oxidative stress, and genomic instability, promoting tumor initiation.
- Accumulation of p62 is a key mechanism through which autophagy deficiency drives liver tumor progression.
