A novel anti-cancer mechanism by exosome release suppression

Poor prognosis of gastric cancer is related to not only malignancy of gastric cancer cells, but also the tumor microenvironment. Thus drugs, which can inhibit both of them, are urgently needed to be explored. Studies on effect of Proton-pump inhibitors (PPIs) in anti-neoplasms are increasing, but is rare in gastric in gastric cancer. Here researchers at the Tianjin Medical University Cancer Institute and Hospital, investigated how the gastric cancer microenvironment is regulated by PPIs. The objective response rate of gastric cancer patients in hospital treated by PPIs is investigated. PPIs’ effects were further explored by observing the change of microRNAs, cytokines, cellular apoptosis. Bioinformatic pathway analysis of microarray was used to discover the pathway involved in PPIs’ regulation of gastric cancer microenvironments. Immunoblotting assays and qRT-PCR were used to define molecular events with PPIs treatment.

The researchers report here that PPIs can improve the prognosis of advanced gastric cancer patients; and inhibit the progress of gastric cancer both in vivo and in vitro. Moreover, high dose of PPIs can regulate the pathway associated with tumor malignancy and microenvironment via inhibiting the release of exosomes, which packed microRNAs. PPIs can inhibit the transformation of CAFs (cancer associated fibroblasts) and cytokines released from CAFs. In addition, PPIs inhibit the malignancy of gastric cancer through regulating HIF-1α-FOXO1 axis. High dose of PPIs can inhibit malignancy of gastric cancer and regulate its surrounding tumor microenvironment. This finding suggests that PPIs maybe of potential value as a therapeutic tool for treatment of gastric cancer.

PPIs inhibited the release of exosomes and exosomes related miRNA
and regulated tumor microenvironment though regulating exosomes

E. SGC7901 cells were cultured with the medium of HFF-1 cell, which were treated with exosome of SGC7901 cells (80 ug/ml of PPI or PBS (control) treated for 24 h). Migration and invasion of SGC-7901 cells were tested by transwell assays (n=3). F. HFF-1 cell were treated with exosome of SGC7901 cells (80 ug/ml of PPI or PBS (control) treated for 24 h), and secreted cytokine were tested by Human Cytokine Array (n=3). G. The unsupervised hierarchical clustering analysis (microarray) of de-regulated miRNAs of exosome. The left is control group and right is the PPIs group.

Guan XW, Zhao F, Wang JY, Wang HY, Ge SH, Wang X, Zhang L, Liu R, Ba Y, Li HL, Deng T, Zhou LK, Bai M, Ning T, Zhang HY, Huang DZ. (2017) Tumor microenvironment interruption: a novel anti-cancer mechanism of Proton-pump inhibitor in gastric cancer by suppressing the release of microRNA-carrying exosomes. Am J Cancer Res 7(9):1913-1925. [article]

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