Role of Helicobacter pylori in gastric cancer: Updates

Abstract

Helicobacter pylori (H. pylori) infection is highly prevalent in human, affecting nearly half of the world's population; however, infection remains asymptomatic in majority of population. During its co-existence with humans, H. pylori has evolved various strategies to maintain a mild gastritis and limit the immune response of host. On the other side, presence of H. pylori is also associated with increased risk for the development of various gastric pathologies including gastric cancer (GC). A complex combination of host genetics, environmental agents, and bacterial virulence factors are considered to determine the susceptibility as well as the severity of outcome in a subset of individuals. GC is one of the most common cancers and considered as the third most common cause of cancer related death worldwide. Many studies had proved H. pylori as an important risk factor in the development of non-cardia GC. Although both H. pylori infection and GC are showing decreasing trends in the developed world, they still remain a major threat to human population in the developing countries. The current review attempts to highlight recent progress in the field of research on H. pylori induced GC and aims to provide brief insight into H. pylori pathogenesis, the role of major virulence factors of H. pylori that modulates the host environment and transform the normal gastric epithelium to neoplastic one. This review also emphasizes on the mechanistic understanding of how colonization and various virulence attributes of H. pylori as well as the host innate and adaptive immune responses modulate the diverse signaling pathways that leads to different disease outcomes including GC.

Keywords: Cag pathogenicity island; Gastric cancer; Gastric mucosa; Helicobacter pylori; Type IV secretion system.

Figure 1

Interaction between Helicobaceter pylori type IV secretion system and virulence determinants such as CagA, CagL, lipopolysaccharides, pepetidoglycan and vacuolating cytotoxin gene, with mucosal epithelial cells, resulting in alteration of signal pathways, cell polarity disruption and vaccuolation, which ultimately leads to death. T4SS: Type IV secretion system; LPS: Lipopolysaccharides; PGN: Pepetidoglycan; VacA: Vacuolating cytotoxin; CagPAI: Cag pathogenicity island.

Figure 2

Combination of host, bacterial and environmental factors, which act in a synergetic way, resulting in development of precancerous cascade that ultimately leads to development of gastric cancer. ZO-1: Zonula occludens 1; CagPAI: Cag pathogenicity island; JAM: Junctional adhesion molecule; VacA: Vacuolating cytotoxin; Cytc: Cytochrome.

Figure 3

Schematic representation of multiple pathways of Helicobacter pylori pathogenesis involved type IV secretion system and internalization of virulence determinants like CagA and oncoproteins; CagA-phosphorylation dependent and CagA-phosphorylation independent pathways leads to cytoskeletal reorganization, increase proinflammatory and mitogenic gene expression. Another major virulent factor, VacA is responsible for alteration of junction and cell polarity by binding with tight junction molecules such as E-cadherin, ZO. VacA also causes mitochondrial membranes depolarization, Cytc release from mitochondria to cytosol and caspase-3 activation followed by cell apoptosis. T4SS: Type IV secretion system; VacA: Vacuolating cytotoxin; ZO: Zonaoccludans; Cytc: Cytochrome; H. pylori: Helicobacter pylori.

Figure 4

Representation of Helicobaceter pylori major virulence factor, vacuolating cytotoxin containing three domain 1: signal sequence(S) 2: middle region (m) 3: recently identified intermediate region (i) s, m and i region are further stratified into the subtypes s1, s2, m1, m2 and i1, i2 respectively. TLR4: Toll like receptor 4; T4SS: Type IV secretion system; VacA: Vacuolating cytotoxin; CagPAI: Cag pathogenicity island; GC: Gastric cancer; ROS: Reactive oxygen species.

Figure 5

Vacuolating cytotoxin of Helicobacter pylori may have any combination of signal sequence and mid region with different virulence activities as stated above. Vac: Vacuolating cytotoxin.