Autophagy in colorectal cancer: An important switch from physiology to pathology

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.

Keywords: Autophagy; Carcinogenesis; Colorectal cancer; Gene; Protein.

Figure 1

Morphological steps of the autophagy process. Autophagy is initiated with the formation of a phagophore, which sequesters cellular material in a double-membrane vesicle called an autophagosome. The autophagosome fuses with lysosomes to form an autolysosome.

Figure 2

The dual and contradictory roles of autophagy in cancer. Autophagy can potentially act as either a promoter or an inhibitor during the transformation from normal cell to malignant cell. Autophagy supports tumor formation by providing an alternative energy source, increasing drug resistance, inhibiting cell death, promoting the survival of tumor cells in a dormant state and ensuring the maintenance of cancer stem cell compartments. Autophagy protects normal cells from malignant transformation by removing damaged organelles and proteins, reducing DNA damage and reactive oxygen species, supporting genomic stability, promoting autophagic cell death, limiting inflammation and stimulating the clearance of intracellular pathogens.