Alteration of angiogenesis in Helicobacter heilmannii‐induced mucosa‐associated lymphoid tissue lymphoma: Interaction with c‐Met and hepatocyte growth factor

Abstract

Background and Aim: The hepatocyte growth factor (HGF)/c-Met pathway has attracted attention in the formation of malignant tumors, as HGF secreted from the microcirculatory components as well as residing macrophages has been suggested to act on the c-Met receptors of cancer cells to decrease apoptosis and increase proliferation, invasion, and metastasis. The present study was undertaken to elucidate the interaction of the gastric, hepatic, and pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma induced by Helicobacter heilmannii infection with c-Met and HGF. Methods: C57BL/6 female mice, infected with H. heilmannii for 3 months were used. The localization of the HGF, c-Met, and HGF activator immunoreactivities was observed by the indirect immunohistochemical methods. In addition, the effect of c-Met antibody and c-Met inhibitor, PHA-665752, was also investigated. Results: c-Met immunoreactivity was found in the lymphocytes composing the MALT lymphoma, and HGF immunoreactivity was recognized mostly in the endothelial cells and macrophages in the MALT lymphoma. HGFA was localized on mesenchymal cells other than the lymphocytes. The administration of the antibody against c-Met or the c-Met inhibitor to the infected mice induced the significant suppression of hepatic and pulmonary MALT lymphoma, while the gastric MALT lymphoma showed only a tendency to decrease in size, while the active caspase 3 positive cells markedly decreased in the gastric, hepatic, and pulmonary MALT lymphoma after the treatment with the c-Met antibody or the c-Met antagonist. Conclusions: HGF and c-Met pathway were suggested to contribute to the lymphomagenesis in the MALT lymphoma after H. heilmannii infection.

Emerging treatments in neurogastroenterology: Acotiamade, a novel treatment option for functional dyspepsia

“…The efficacy of traditional herbal medicines in the treatment of FD has also been reported . For example, we conducted a multicenter, randomized, placebo‐controlled, parallel‐group trial to investigate the effect of rikkunshito, a traditional Japanese herbal medicine, on FD . In this study, especially, epigastric pain was improved in the rikkunshito group.…”

“…Membrane‐binding assay analysis has revealed that acotiamide has binding affinity with muscarinic M 1 and M 2 , but not M 3 receptors . Acotiamide has antagonistic effects on M 1 and M 2 receptors . M 3 receptors are expressed in the stomach and stimulate gastric motility.…”

The role of HGF/c-MET signaling pathway in lymphoma

“…c-MET was found in the lymphocytes composing mucosa-associated lymphoid tissue (MALT) lymphoma, and HGF was recognized mostly in the endothelial cells and macrophages in the MALT lymphoma [41]. HGF activator was localized on the mesenchymal cells other than the lymphocytes.…”

“…HGF activator was localized on the mesenchymal cells other than the lymphocytes. c-MET inhibition suppressed the hepatic and pulmonary MALT lymphoma, while the gastric MALT lymphoma showed only a tendency to decrease in size [41]. …”

“…PHA665752 treatment induced the activation of Caspase-9, Caspase-3, and downstream PARP cleavage, the hallmarks of cells undergoing apoptosis [18]. PHA-665752 was also injected intraperitoneally in mice with MALT lymphoma, which induced the significant decrease in the hepatic and pulmonary MALT lymphoma size and the marked activation of Caspase 3 in fundic, hepatic, and pulmonary MALT lymphoma [41]. NKTCL cell lines treated with ARQ197, an ATP-non-competitive selective c-MET inhibitor which is currently in phase 3 clinical trials in NSCLC patients, reduced the proliferative response by approximately 50% in two of three cell lines, indicating that the HGF/c-MET signaling is partly responsible for NKTCL proliferation [49].…”