Abstract
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as H. pylori-derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the H. pylori proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment.
Highlights
Cancer is a leading cause of premature death in 127 countries, and if current numbers and trends continue, cancer could overtake cardiovascular disease in this century [1]
This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment
Erosive gastritis can be caused by stress, alcohol, or chemical drugs, up to 89% of non-cardia gastric cancers are attributable to H. pylori infection [3]
Summary
Cancer is a leading cause of premature death in 127 countries, and if current numbers and trends continue, cancer could overtake cardiovascular disease in this century [1]. Cleavage of occludin and members of the claudin protein family can occur through upregulation of host proteases, such as MMP2, MMP7, and MMP9, and is usually associated with an increase in epithelial or endothelial permeability [70,74,100,101,102,103] These proteases were shown to be induced in response to H. pylori infection [39,65] and in gastric cancer tissue [104,105], a direct role of these proteases in disruption of the gastric epithelium has not been established so far. In the context of H. pylori infections, upregulation of calpain and caspase-3 induced intracellular E-cadherin cleavage, resulting in disintegration of the E-cadherin/catenin complex and increased apoptosis of gastric epithelial cells [82,83,85]. It can be speculated that a higher efficiency in basolateral CagA delivery by H. pylori is linked to a higher risk for developing gastric cancer [59]
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