Autophagy in malignant transformation and cancer progression

Abstract

Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

Keywords: Beclin 1; KRAS; adaptive stress responses; inflammation; mitophagy.

Figure 1

General organization of autophagic responses Autophagy initiates with the progressive segregation of cytoplasmic material by double-membraned structures commonly known as phagophores or isolation membranes. Phagophores nucleate from the endoplasmic reticulum (ER), but several other membranous organelles have been shown to contribute to their elongation, including the Golgi apparatus, ER-Golgi intermediate compartment (ERGIC), plasma membrane, mitochondria and recycling endosomes. Completely sealed phagophores, which are known as autophagosomes, fuse with lysosomes to form autolysosomes. This promotes the activation of lysosomal hydrolases and hence causes the breakdown of the autophagosomal cargo. The products of these catabolic reactions reach the cytosol via transporters of the lysosomal membrane and are recycled by anabolic or bioenergetic circuitries.

Figure 2

Oncosuppressive functions of autophagy Autophagy has been proposed to suppress malignant transformation by several mechanisms, including: (1) the preservation of genetic/genomic stability; (2) the disposal of endogenous sources of potentially mutagenic reactive oxygen species (ROS); (3) the maintenance of normal bioenergetic functions; (4) the degradation of oncogenic proteins; (5) cell-endogenous antiviral and antibacterial effects; (6) the optimal activation of oncogene-induced senescence (OIS) and oncogene-induced cell death (OICD); (7) the maintenance of a normal stem cell compartment; (8) multipronged anti-inflammatory functions; and (9) a key role in the elicitation and execution of anticancer immunosurveillance. ABL1, ABL proto-oncogene 1; APC, antigen-presenting cell; BCL10, B-cell CLL/lymphoma 10; BCR, breakpoint cluster region; CTL, cytotoxic T lymphocyte; TP53^mut, mutant tumor protein p53; PML, promyelocytic leukemia; RARA, retinoic acid receptor, alpha; RHOA, ras homolog family member.

Figure 3

Tumor-supporting functions of autophagy Once malignant transformation has occurred, autophagy is believed to promote tumor progression and resistance to therapy. Such tumor-supporting functions reflects the ability of autophagy to: (1) improve the resistance of cancer cells to endogenous conditions that normally provoke cell death, such as the detachment from the basal membrane, hypoxia and nutrient deprivation; (2) render transformed cells less sensitive to therapy-induced cell death; (3) sustain the survival of cancer cells that enter a state of dormancy or senescence in response to therapy; and (4) ensure the maintenance of the cancer stem cell compartment. EMT, epithelial-to-mesenchymal transition.

Figure 4

Autophagy in malignant transformation and tumor progression (A) Healthy cells appear to be protected from malignant transformation by proficient autophagic responses. Conversely, autophagy promotes tumor progression and therapy resistance in a variety of models. Thus, the transition of a healthy cell toward a metastatic and therapy-insensitive neoplasm may involve a temporary (but not a stable) loss in autophagy competence. The mechanisms underlying the restoration of proficient autophagic responses after malignant transformation remain to be elucidated. (B, C) In specific settings, oncogenesis and tumor progression may rely on a permanent loss (B) or gain (C) of autophagic proficiency.