Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Abstract

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.

Deregulation of miRNA in Helicobacter pylori-Induced Gastric MALT Lymphoma: From Mice to Human

“…As previous studies have suggested that H. pylori cytotoxin-associated gene A (CagA) directly participate to the lymphomagenesis of H. pylori -dependent GML [75,76,77], it could also be of major interest to determine if CagA could participate in the deregulation of these miRNAs.…”

Immunomodulatory treatment for mucosa‐associated lymphoid tissue lymphoma (MALT lymphoma)

“…According to the current concept, MALT lymphomagenesis is mediated via a multi‐step sequence initiated by H. pylori infection‐associated development of acquired MALT in the gastric mucosa accompanied by invasion of immune effector cells and downstream increased production of pro‐inflammatory mediators 16‐20 . Importantly, H. pylori is not able to directly stimulate B‐cells, and thus differentiation and accrual of H. pylori reactive T‐cells (mostly T H2 and T regs ) followed by persistent antigenic stimulation play a crucial role in this process and are mainly responsible for the perpetual activation of the marginal zone B‐cells eventually triggering the switch from polyclonal to monoclonal expansion 16,17,21,22 . This assumption has been underlined by studies showing that successful cultivation of lymphoma cells is only possible in co‐culture of H. pylori specific T‐cells, while the lymphoma cells decline and express less interleukins (IL) if deprived of H. pylori specific T‐cells 16,22 .…”

Cortactin: A Major Cellular Target of the Gastric Carcinogen Helicobacter pylori

“…When the pathogen is eradicated by antibiotic treatment, MALT lymphoma regresses in over 75% of cases, suggesting that continuous presence of the bacteria is required to maintain malignancy potential [13,14]. In addition, eradication of the pathogen significantly reduces the chance of recurring gastritis and peptic ulceration [15,16]. According to 2018 estimates by the World Health Organization (WHO) and Global Burden of Cancer Study (GLOBOCAN), gastric cancer is the third leading cause of annual deaths due to cancer worldwide [17].…”