Independent Signaling of Hepatoma Derived Growth Factor and Tumor Necrosis Factor-Alpha in Human Gastric Cancer Organoids Infected by Helicobacter pylori

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFa) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFa secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFa and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFa decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFa decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFa during infection by H. pylori. Recombinant HDGF and TNFa inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFa are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Automated summary

By preparing three-dimensional organoids of human stomach cancers and studying the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori), we found that hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFa) had effects on the growth and invasion activity of H. pylori-infected gastric cancer organoids. HDGF controlled the growth of organoids in a species-specific manner, while TNFa decreased cell viability in H. pylori-infected organoids. Additionally, HDGF controlled the invasion activity of H. pylori-infected organoids in a species-dependent manner, whereas TNFa decreased invasion activities of most organoids.