Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance

Abstract

Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.

Keywords: autophagy; colorectal cancer; epithelial-mesenchymal transition; metastasis; therapeutic resistance; tumor microenvironment.

Figure 1

A diagrammatic representation of the macroautophagy (also known as autophagy) process is shown. A phagophore forms in autophagy that sequester cytoplasmic material in a vesicle that later matures into an autophagosome, which then fuses with lysosomes to form an autolysosome, where the sequestered material is degraded. The autophagy process takes place in several steps such as Initiation, Nucleation, Elongation, Maturation, Fusion, and Degradation. The autophagy process can be blocked at various steps with the help of autophagy inhibitors listed in the red color.

Figure 2

EMT is promoted by hypoxia-dependent autophagy in CRC. As the tumor progresses, hypoxia becomes more prevalent. A growing tumor triggers autophagy as an adaptive survival mechanism. Autophagy increases the plasticity of tumor cells, causing them to acquire mesenchymal characteristics. In CRC hypoxia-induced autophagy target SIRT1 promotes EMT process and hypoxia-induced autophagy inhibition by GRIM-19 prevents EMT. However, whether hypoxia-induced autophagy can upregulate itself by downregulating the expression of GRIM-19 is not known.

Figure 3

Dichotomous role of autophagy in CRC. Autophagy plays a complex and context-dependent role. On one hand, it can protect against abnormal survival by promoting autophagic death of tumor cells, maintain homeostasis and remove dysfunctional organelles in early stages, while on the other hand, it can promote tumor growth by favoring immune evasion, EMT, angiogenesis, and resisting the therapeutic effects when cancer has advanced.