Autophagy: cancer's friend or foe?

Abstract

The functional relevance of autophagy in tumor formation and progression remains controversial. Autophagy can promote tumor suppression during cancer initiation and protect tumors during progression. Autophagy-associated cell death may act as a tumor suppressor, with several autophagy-related genes deleted in cancers. Loss of autophagy induces genomic instability and necrosis with inflammation in mouse tumor models. Conversely, autophagy enhances survival of tumor cells subjected to metabolic stress and may promote metastasis by enhancing tumor cell survival under environmental stress. Unraveling the complex molecular regulation and multiple diverse roles of autophagy is pivotal in guiding development of rational and novel cancer therapies.

Figure 2.1

Molecular events in the autophagy pathway. A stress response, such as nutrient withdrawal, causes cells to initiate autophagy. The stress sensor TOR kinase remains inactivated in low-nutrient condition and maintains hypophosphorylated Atg13. Atg1/Ulk1 interacts with Atg13 and Atg17 and regulates transmembrane protein Atg9 involved in lipid import from cellular organelles to act as a “phagophore” formation initiator. Next, Vps34/Beclin1 converts PI to PI3P followed by Atg5–Atg12 conjugation and interaction with Atg16L resulting in multimerization at the phagophore and formation of nascent curvature; coupled to these changes, LC3 processing helps elongation and expansion. Random or selective cargoes are targeted for degradation, followed by formation of a complete double-membrane ring called an “autophagosome.” Lysosomes dock and fuse with the autophagosome, forming an “autolysosome” where degraded cargoes generate amino and fatty acids to be transported back into the cytoplasmic pool. Autophagy acts as a primary response promoting cell viability and serving a cytoprotective role and upon stress removal the cell resumes normal function. However, extreme stress pushes the cell to cross the point of no return and commits it toward autophagic cell death (type II programmed cell death, PCD).

Figure 2.2

Model of the primary events involved in the metastatic cascade. The metastatic process is complex and involves numerous changes in cellular phenotype resulting from both genetic and epigenetic modifications of the cancer genome. The process is initiated by the spread of cancer cells from a primary tumor site to other regions in the body. Cells initiate growth as primary tumors in the epithelium and with genetic and epigenetic modifications, subsets of tumor cells develop metastatic properties allowing them to degrade the basal layer and invade the blood stream (Intravasation). A small percentage of tumor cells escape into blood vessels (Extravasation), survive in the bloodstream, adhere to new target organ sites, and ultimately form secondary tumors (metastases) in distant organ or tissue sites. A key component of both the primary and secondary expansion of the tumor and metastases is the development of a new supply of blood vessels, that is, angiogenesis. Taken from Das et al. (2012).

Figure 2.3

Role of autophagy at different stages of cancer. During the initial phase of cancer development, autophagy-related cell death has been regarded as a primary mechanism for tumor suppression. Moreover, autophagy also restricts necrosis and inflammation thus limiting invasion and dissemination of tumor cells from a primary site, resulting in restriction of metastasis at a premature step. Moreover, lethal (toxic) autophagy directly causes the release of immunomodulatory factors such as HMGB-1 from dead tumor cells, which activates immune response and restricts metastasis by inhibiting protumorigenic responses. On the other hand, altered energy metabolism and TRAIL-resistant phenomena of tumor cells are maintained through protective autophagy during tumor progression. Similarly, autophagy may promote metastasis by enhancing tumor cell fitness in response to environmental stresses, such as anoikis during metastatic progression. Protective autophagy is involved in maintaining dormant tumor cells and promoting their survival under stressful conditions. The exact role of autophagy in cancer stem cells is unclear in tumor progression. Finally, tumor cells maintain protective autophagy through activation of HIF-1 (hypoxia-inducible factors) and AMPK (5′-AMP-activated protein kinase) in apoptosis deficient and long-term metabolic stress conditions, in a full-blown cancer.

Figure 2.4

Astrocyte elevated gene-1 (AEG-1) and protective autophagy. Model illustrating the possible molecular mechanism of AEG-1-mediated protective autophagy, which promotes escape from apoptosis and resistance to chemotherapy. Taken from Bhutia, Kegelman, et al. (2010).