Effect of proton pump inhibitors on the occurrence and development of gastric cancer and the polarization of macrophages in the microenvironment to M2-type.

Abstract

437 Background: Long-term use of Proton pump inhibitors was associated with an increased gastric cancer(GC) risk in subjects even after HP eradication therapy. In contrast some basic research showed that PPI inhibited the growth of GC. In the tumor-microenvironment (TME), macrophages that are recruited around the tumor are activated to form the tumor-associated macrophages (TAMs), which are the most abundant mononuclear cells in the tumor infiltrating leukocytes. Many studies have shown that TAMs are associated with poor prognosis of tumors. Methods: Immunohistochemistry was used to detect the phenotype of macrophages in patients with gastric cancer treated with PPI or without PPI. Transcriptomics sequencing analyzed the signal pathways that were highly expressed in PPI-treated gastric cancer for further exploring the mechanism of PPI's main role in gastric cancer cells. In vitro, explore the effects of PPI on gastric cancer cells and the next step on macrophages. The effects of PPI on the growth of gastric cancer and the degree of infiltration and phenotype transformation of macrophages were verified by in vivo experiments. Results: In the gastric cancer tissues treated with PPI, the macrophage phenotype is mostly M2 type, thereby exerting a cancer promoting effects. Transcriptome results showed high expression of genes associated with endoplasmic reticulum stress in gastric cancer tissues after PPI treatment, compared with patients who were not treated with PPI. Among them, GRP78 is a classic marker of endoplasmic reticulum stress. It was not only highly expressed in gastric cancer treated by PPI, but also acted on macrophages through exosomes secreted by gastric cancer cells, and caused macrophage to polarize to M2. Conclusions: PPI caused GC cells to overexpress GRP78 which was secrete into the microenvironment through exosomes, thereby transforming macrophages into M2 type under the action of GRP78. Finally M2 type macrophages promoted the progression of gastric cancer.