Matrix Metalloproteinases in Helicobacter pylori-Associated Gastritis and Gastric Cancer

Abstract

Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric atrophy, which can progress stepwise to gastric cancer. Matrix metalloproteinases (MMPs) actively participate in the pathology development. The further progression of gastric cancer seems to be less dependent on bacteria but of intra-tumor cell dynamics. Bioinformatics data confirmed an important role of the extracellular matrix constituents and specific MMPs in stomach carcinoma invasion and metastasis, and revised their potential as predictors of the disease outcome. In this review, we describe, in detail, the impact of MMPs in H. pylori-associated gastritis and gastric cancer.

Keywords: MAP kinases; NF-κB; inflammation; type IV secretion system.

Figure 1

Signaling pathways pivotal for MMPs expression and MMPs-related processes in gastritis and gastric cancer. In tumor cell, the NF-κB, JNK and ERK MAPK pathways activated in response to H. pylori and cytokines are not shown for simplicity. The transcription factors and their regulators important for expression of the EMT-related genes and discussed in the review are depicted in the tumor cell. The immune cells are recruited to the tissue and release a big number of mediators, including MMPs. MMPs from different cells populations activate each other, participate in matrix remodeling, regulate focal adhesion complexes and shed proteins in cellular junctions. It leads to disturbances in the cellular contacts and restructures actin, which impacts the cellular motility. MMPs can also activate cytokines and growth factors embedded within the extracellular matrix. In the tumor microenvironment, both cancer cells and tumor-associated immune cells keep producing the growth factors and MMPs, supporting the motility and invasion of tumor cells. AJ, adherens junctions; GFs, growth factors; CR, cytokine receptor; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EpC, epithelial cell, HP, H. pylori; LP, lamina propria; RTK, receptor tyrosine kinase; TGs, tight junctions.