Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers

Abstract

The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers.

Inactivation of Autophagy in Keratinocytes Reduces Tumor Growth in Mouse Models of Epithelial Skin Cancer

“…The tumor cells’ dependency on autophagy for persistent growth is well-explained by the central function of autophagy as a key component of intracellular recycling. Various models have suggested that autophagy increases the fitness of neoplastic cells, in particular when the supply of nutrients decreases in large tumors [ 44 , 45 , 46 ]. However, autophagy in the cells of the tumor microenvironment also supports the growth of tumors by enhancing the generation and secretion of nutrients [ 47 , 48 ] and the autophagy-dependent signaling processes in non-malignant cells affect their interactions with tumor cells [ 49 , 50 ].…”

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

“…Several chemotherapies stimulate both apoptosis in cancer cells and autophagy through ROS activation [ 152 ]. In addition, in vivo experiments show that autophagy loss can trigger extrinsic cell signaling of tumor cells, including facilitating the pro-tumorigenic inflammatory microenvironment [ 153 , 154 ]. Autophagy is regulated by different pathways, including the mTOR pathway.…”

The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches

“…In addition to this, mitochondria removal mechanisms which permit the elimination of damaged and excessed mitochondria guarantees the preservation of a healthy mitochondrial pool. Among the diverse mechanisms regulating this mitochondrial turnover, the selective form of autophagy pathway, known as mitophagy [ 85 ], represents the primary line of intervention. Dysfunctions in such mitochondrial-related pathways may be cause and consequence of several disorders [ 86 , 87 , 88 , 89 ] and can be also related to a hypoxic condition.…”