**13.3. How does autophagy suppress tumourigenesis?**

The combined data presented above strongly support the idea that autophagy functions as a tumour suppressor process. Consistent with this, oncogenes that have a role in autophagy are potent inhibitors of this process. Although the molecular mechanisms by which autophagy functions in tumour suppression are poorly defined, at least two mechanisms have been described:

a. Autophagy maintains the integrity of the genome

The first hypothesis is that autophagy may function as a housekeeping pathway to exert the quality control of organelles, proteins and DNA. Mathews and colleague observed that in autophagy deficient tumour cells, metabolic stress promotes the accumulation of p62, damaged mitochondria and ROS generation, promoting genomic instability and leading to oncogene activation and tumour progression [157,158]. Furthermore, immortalized mouse epithelial cells with a defect in ATG genes (loss of Beclin 1 or Atg 5) display increased DNA damage, centrosome abnormalities, numerical and structural chromosomal abnormalities and gene amplification, especially after ischemic stress.

However, the mechanisms through which autophagy preserves the integrity of the genome remains elusive. One possibility could be that autophagy may contribute to cell cycle regulation, for example by degrading organelles and/or proteins involved in the cell cycle checkpoints [159]. Another possibility is that autophagy might simply function at a more general level to ensure the minimal amount of ATP and other metabolites required for DNA repair. Finally, autophagy may act by removing old and/or damaged organelles (for example, uncoupled mitochondria) which may act as a source of genotoxic chemical species such as ROS.

b. Autophagy limits necrosis-mediated inflammation

Necrosis normally results from physical injury in which the cell lyses and releases its intracellular contents, which activate the innate immune system and a wound-healing response [160]. As a result, inflammatory cells are recruited and cytokines are released to promote cell growth to replace the damaged tissue [161,162].

In contrast, apoptosis may be the preferred means of cell demise for cells upon metabolic stress, as cells are eliminated without inflammation. However, in cancer cells with a defect in apoptosis, autophagy is induced for cell survival. Through autophagy, cells eliminate damaged organelles and may maintain their normal cellular function under adverse conditions of fluctuating oxygen and nutrient supply. However, this beneficial effect of autophagy functions during short term interruptions in nutrient availability, as in the long term (excess of autophagy) it can possibly lead to cell death.

A high proportion of tumours have been seen to present a defect both in autophagy and apoptosis. Degenhardt and colleagues have shown that the inhibition of both processes under conditions of metabolic stress generates a necrotic cell-death, suggesting that apoptosis and autophagy function to limit necrosis [163]. In these necrotic tumours a persistent inflammatory infiltration and cytokine production exists, which is thought to promote tumour growth and thus, is associated with poor prognosis.
