Autophagy is the primary means for the degradation of cytoplasmic constituents in the lysosome. Autophagy is up-regulated by nutrient limitation and is critically important for maintenance of the amino acid pool during the starvation period and preimplantation development. On the other hand, autophagy is also important for intracellular protein quality control particularly in the brain and liver, which has been suggested by studies using tissue-specific autophagy-deficient mice. However, because complete autophagy suppression in mice causes neonatal lethality, the long-term effects of defects in autophagy have not been analyzed.

To overcome the lethal phenotype of autophagy-deficient mice, we generated mice with systemic mosaic deletion of Atg5, in which only a small population of cells were autophagy-defective. These mice are viable for more than 19 months and develop multiple tumors only in the liver, suggesting that autophagy is important for suppression of spontaneous tumorigenesis. These tumor cells originate autophagy-deficient hepatocytes, and show mitochondrial swelling, p62 accumulation, and oxidative stress and genomic damage responses. Furthermore, liver-specific Atg7-/- mice also developed liver tumors, which were reduced in size by simultaneous deletion of p62, a selective autophagy substrate. These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and p62 accumulation contributes to tumor progression.

The present study proposes a novel mechanism of tumorigenesis; defects in autophagy-dependent quality control of cytoplasmic contents (i.e. proteins and organelles) causes liver tumors, which may be relevant to human cancer pathogenesis. This study also provides a novel tool to study autophagy in a non-biased way. Since autophagy should be involved in a variety of physiological and pathological processes, the Atg5 mosaic mice would be useful to explore novel roles of autophagy.

Autophagy-deficient mice develop multiple liver tumors
Akito Takamura, Masaaki Komatsu, Taichi Hara, Ayako Sakamoto, Chieko Kishi, Satoshi Waguri, Yoshinobu Eishi, Okio Hino, Keiji Tanaka, and Noboru Mizushima
Genes Dev. 2011;25 795-800
http://genesdev.cshlp.org/cgi/content/abstract/25/8/795?etoc