Proteolytic Landscapes in Gastric Pathology and Cancerogenesis

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.

Deciphering Mechanisms of Action of Sortilin/Neurotensin Receptor-3 in the Proliferation Regulation of Colorectal and Other Cancers

“…Indeed, the use of BB3103, the ADAM10 (A Desintegrin And Metalloprotease) inhibitor, was shown to block the formation of sSortilin/NTSR3 by HT29 cells [ 14 ]. Although clinical trials targeting MMPs have been canceled in phase I or in phase III for numerous inhibitors, increasing the selectivity for specific MMPs could offer a useful objective for the further development of selective treatments for each type of cancer (for a review see, [ 96 ]).…”

Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches

“…E-cadherin interacts directly or indirectly with many other membrane components (e.g., tight junctions, gap junctions, desmosomes, integrin-based adhesions, and pathogenetic proteins) [ 36 ]. The extracellular fragment of E-cadherin can be cleaved by membrane-bound metalloproteinases from the membrane after proteolysis of E-cadherin [ 40 ]. Soluble E-cadherin controls multiple signaling pathways via paracrine and autocrine signaling.…”