Role of autophagy in gastric carcinogenesis

Abstract

Gastric cancer represents a common and highly fatal malignancy, and thus a pathophysiology-based reconsideration is necessary, given the absence of efficient therapeutic regimens. In this regard, emerging data reveal a significant role of autophagy in gastric oncogenesis, progression, metastasis and chemoresistance. Although autophagy comprises a normal primordial process, ensuring cellular homeostasis under energy depletion and stress conditions, alterations at any stage of the complex regulatory system could stimulate a tumorigenic and promoting cascade. Among others, Helicobacter pylori infection induces a variety of signaling molecules modifying autophagy, during acute infection or after chronic autophagy degeneration. Subsequently, defective autophagy allows malignant transformation and upon cancer establishment, an overactive autophagy is stimulated. This overexpressed autophagy provides energy supplies and resistance mechanisms to gastric cancer cells against hosts defenses and anticancer treatment. This review interprets the implicated autophagic pathways in normal cells and in gastric cancer to illuminate the potential preventive, therapeutic and prognostic benefits of understanding and intervening autophagy.

Keywords: Autophagy; Chemoresistance; Gastric cancer; Helicobacter pylori; Prognosis.

Figure 1

Autophagy activity pattern in normal and gastric malignant cells. Under normal conditions autophagy is strictly regulated in response to stimuli to preserve cytoplasm homeostasis. Excessive downregulation promotes gastric carcinogenesis and upon malignant transformation, the autophagic over activity contributes to progression, metastasis and negative prognosis. H. pylori: Helicobacter pylori.

Figure 2

The role of autophagy in normal and malignant gastric cells in response to specific stimuli. Normal stomach cell-related autophagy appears to inhibit oncogenesis and preserve homeostasis, whereas its downregulation facilitates malignant transformation. Gastric cancer cells express autophagy promoters to yield their energy supplementation, and thus progression, metastasis, negative overall survival and chemoresistance. Several autophagy inhibitors have been recognized to act against malignant cells, thus representing promising targets for future therapeutics. ATGs: Autophagy-related genes; DAPK3: Death-associated protein kinase 3; CagA: Cytotoxin-associated gene A; H. pylori: Helicobacter pylori; miR: MicroRNA; SIRT: Sirtuin; VacA: Vacuolating cytotoxin.