One consequence of autophagy defects in tumors is impaired survival in stress, which results in chronic tumor cell death (14
). Superficially, stimulation of cell death in tumors may appear to be a desirable outcome. However, persistent chronic cell death elicits an inflammatory response that can be pro-tumorigenic (36
). Dead cells, particularly apoptosis-defective cells that undergo necrotic cell death releasing cellular contents, potently activating a pro-inflammatory immune response (37
). The nuclear protein high mobility group protein B1 (HMGB1) is released from necrotic cells where it is a ligand for the cell surface receptor for advanced glycation endproducts (RAGE) that is a potent activator of NF-κB. Similarly, nucleic acids released from necrotic cells can stimulate inflammation through activation of Toll-like receptors. The presence of these damage-associated molecular patterns (DAMPs) signals tissue damage and inflammation. Thus, tumors can appear as wounds that do not heal, which benefit from the persistent presence of inflammatory cells and cytokines meant to repair tissue damage. In the case of chronic cell death in a tumor, however, the wound does not heal, inflammation does not resolve, and instead tumor growth is enhanced ().
Stimulation of apoptotic cell death in tissues can also be pro-inflammatory and oncogenic. Chronic apoptotic cell death in the liver can trigger inflammation, more tissue damage and an increased risk of HCC (39
). Hepatocyte cell death activates resident macrophages (Kupffer cells) to produce hepatomitigens that stimulate compensatory proliferation. This is a normal reaction to repair tissue damage, but when the underlying cause is persistent (hepatitis virus infection, alcohol consumption, toxins, perhaps defective autophagy), this chronic inflammation promotes tumorigenesis. Thus, acute cell death may be required for tumor eradication while chronic cell death can promote tissue damage, inflammation and tumorigenesis. Interestingly, autophagy defects in mice cause hepatocyte toxicity, liver damage and HCC (6
Autophagy-defective embryonic tissues are impaired for the removal of cell corpses (40
), which raises the potential to prolong pro-inflammatory stimuli through both increased cell death and the failure to eliminate dead cells. Immortal mouse mammary epithelial cells with allelic loss of beclin1
accumulate cell corpses when grown as three-dimensional mammospheres, but if this contributes to inflammation and increased tumorigenesis is not known (15
). Apoptosis-defective tumors with autophagy defects display chronic necrosis and inflammation with dramatic macrophage infiltration, NF-κB activation and cytokine production compared to tumors where autophagy is intact (14
). These findings are consistent with autophagy promoting tumor cell survival and limiting inflammation as a non-cell autonomous means to suppress tumorigenesis. These contrasting tumor cell survival promoting and tumor suppressing activities contribute to autophagy acting as a double-edged sword in the cancer setting ().