Role of autophagy in cancer - PubMed (original) (raw)

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Role of autophagy in cancer

Robin Mathew et al. Nat Rev Cancer. 2007 Dec.

Abstract

Autophagy is a cellular degradation pathway for the clearance of damaged or superfluous proteins and organelles. The recycling of these intracellular constituents also serves as an alternative energy source during periods of metabolic stress to maintain homeostasis and viability. In tumour cells with defects in apoptosis, autophagy allows prolonged survival. Paradoxically, autophagy defects are associated with increased tumorigenesis, but the mechanism behind this has not been determined. Recent evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.

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Figures

Figure 1

Figure 1. Altered capacity for apoptosis and autophagy can dictate cell fate in response to metabolic stress

a | Apoptosis is a common response to metabolic stress in which cells activate caspases and die efficiently. For immortal epithelial cells, metabolic stress triggers apoptosis within 24 to 48 hours,,. Execution of apoptosis occurs in less than an hour and cell viability loss is five to six orders of magnitude. b | Defective autophagy (through loss of BECN1 or ATG5, for example) can increase apoptotic cell death in some cells in response to metabolic stress. In human mammary cells in 3D culture in vitro, this accelerated apoptosis manifests as increased lumen formation in mammary acini . Therefore, preservation of cell metabolism through autophagy might increase the threshold for apoptosis activation. c | In cells with defects in apoptosis, survival in metabolic stress is dependent on autophagy and is prolonged for weeks,,,. During the maintenance phase, activities such as cell division and motility are sustained. Prolonged starvation and progressive autophagy causes cells to gradually shrink in size but restoration of nutrients allows recovery. In the preservation phase, cell division and motility decrease, presumably as a bioenergenic conservation effort, creating the minimal cell that is capable of recovery (MCCR). Eventually, restoration of nutrients fails to allow recovery. In this way, autophagy can be viewed as an interruptible path to cell death. d | Cells with defects in apoptosis and autophagy fail to tolerate metabolic stress, undergo metabolic catastrophe and die by necrosis.

Figure 2

Figure 2. Role of apoptosis and autophagy in tumorigenesis

a | Tumour-initiating mutational events such as oncogene activation promote cell proliferation, but also apoptosis, which limits tumour growth. Following the acquisition of defects in apoptosis, tumour proliferation is sustained in the absence of apoptotic cell death. b | Tumour growth is initially limited by the absence of a blood supply, which can trigger autophagy-mediated survival in the most metabolically stressed tumour regions, commonly the hypoxic center,,. The eventual recruitment of a blood supply cures the tumour of hypoxia and metabolic stress, and the tumour cells formerly surviving through autophagy can emerge to contribute to tumour growth. c | In tumours formed by cells with defects in both apoptosis and autophagy, necrotic cell death is stimulated in metabolically stressed tumour regions and this necrosis is associated with the activation of an inflammatory response, DNA damage and tumour progression,,. Analogous to a wound-healing response, chronic necrosis and inflammation can stimulate angiogenesis and tumour growth–.

Figure 3

Figure 3. Application of autophagy modulation to cancer therapy

a | In apoptosis-defective tumours that are reliant on autophagy to survive metabolic stress, autophagy inhibitors can be used to induce acute necrotic cell death that may be facilitated by proteasome inhibition, enabling tumour eradication. b | In the adjuvant setting, and after elimination of a large proportion of the tumour by radiation and chemotherapy, the remaining cells can reside in a disrupted and stressed environment, susceptible to inhibition of the autophagy survival mechanism. Tumour cells in the process of metastasis can be similarly vulnerable. c | Autophagy stimulators may be therapeutically useful to either promote autophagic cell death or to prevent the damaging effects of autophagy deficiency and mismanagement of metabolic stress leading to DNA damage and tumour progression. By limiting protein, organelle and ultimately DNA damage, autophagy stimulators may suppress tumour progression. In human breast, ovarian and prostate cancers, where allelic loss of BECN1 occurs with high frequency, correction of the autophagy deficiency with autophagy stimulators may delay tumour progression by reducing the rate at which tumour-promoting mutations accumulate.

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