Helicobacter pylori CagA: From Pathogenic Mechanisms to Its Use as an Anti-Cancer Vaccine

Abstract

Helicobacter pylori colonizes the gastric mucosa of more than 50% of the human population, causing chronic inflammation, which however is largely asymptomatic. Nevertheless, H. pylori-infected subjects can develop chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Chronic exposure to the pathogen and its ability to induce epithelial to mesenchymal transition (EMT) through the injection of cytotoxin-associated gene A into gastric epithelial cells may be key triggers of carcinogenesis. By deregulating cell-cell and cell-matrix interactions as well as DNA methylation, histone modifications, expression of micro RNAs, and resistance to apoptosis, EMT can actively contribute to early stages of the cancer formation. Host response to the infection significantly contributes to disease development and the concomitance of particular genotypes of both pathogen and host may turn into the most severe outcomes. T regulatory cells (Treg) have been recently demonstrated to play an important role in H. pylori-related disease development and at the same time the Treg-induced tolerance has been proposed as a possible mechanism that leads to less severe disease. Efficacy of antibiotic therapies of H. pylori infection has significantly dropped. Unfortunately, no vaccine against H. pylori is currently licensed, and protective immunity mechanisms against H. pylori are only partially understood. In spite of promising results obtained in animal models of infection with a number of vaccine candidates, few clinical trials have been conducted so far and with no satisfactory outcomes. However, prophylactic vaccination may be the only means to efficiently prevent H. pylori-associated cancers.

Keywords: CagA; Helicobacter pylori; cancer; epithelial to mesenchymal transition; junctions; type IV secretion system; vaccine.

Figure 1

Schematic of major CagA structural domains and functions. The amino-terminal domain (D1; aa24–aa221) of CagA activates inflammatory responses via NFκB and prevents apoptosis via the tumor suppressor p53. The central domain (D2; aa303–aa644) contains the β1-integrin binding domain, which is required for CagA translocation into the host cell, and a segment of basic aa that tethers CagA to phosphatidylserine in the inner leaflet of the cytoplasmic membrane. The N-terminal binding sequence (NBS) located within the D3 domain (aa645–aa824) binds to the C-terminal binding sequence (CBS) located within the intrinsically unstructured C-terminus to form a loop-like structure that exposes the CM dimerization motifs (blue circles) and the EPIYA motifs (red circles). Both motifs trigger many of the CagA-dependent signaling events including disruption of cell polarity, morphological changes, cell motility, and invasion.

Figure 2

Model of H. pylori-associated carcinogenesis through CagA-induced epithelial to mesenchymal transition (EMT). H. pylori injects CagA into gastric epithelial cells through a type IV secretion system. CagA disrupts cell–cell junctions by targeting the apical junction complex (AJC), causing loss of cell polarity. Thereafter, CagA induces cell motility and formation of actin pseudopodia, invasive behavior with the expression of the matrix metalloproteinase 7 (MMP-7), expression of EMT-associated genes, and resistance to apoptosis. Therefore, life-long exposure of the gastric mucosa to H. pylori and sustained injection of CagA into gastric epithelial cells may provide the epigenetic promoting forces toward carcinogenesis.