Propionibacterium acnes overabundance in gastric cancer promote M2 polarization of macrophages via a TLR4/PI3K/Akt signaling

Abstract

Objective Eradication of Helicobacter pylori (H. pylori) could not completely prevent the progression of gastric cancer (GC), suggesting that non-H. pylori bacteria may participate in the carcinogenesis of GC. The dysbiosis of microbiota in the stomach of GC has gradually been investigated, while the detailed mechanism that promotes GC in this process has not been elucidated. We aimed to identify a non-H. pylori bacteria that contribute to GC. Design GC tissues and adjacent normal tissues were collected to identify bacteria that significantly increased in GC tissues by 16S rRNA gene sequencing and fluorescence in situ hybridization (FISH) analysis. CCK8, wound healing assay, and trans-well assay were performed to analyze the tumor-promoting effect of this bacteria. Next, we detailed the mechanism for tumor-promoting effect of the bacteria by immunofluorescence, RT-qPCR, and western-blotting analysis. ResultsComparing the microbial community from GC tissues and adjacent normal tissues, we found that Propionibacterium acnes (P. acnes) significantly increased in GC tissues, especially in H. pylori-negative tissues. We further found that the abundance of P. acnes correlated with TNM stages of GC patients. Interestingly, condition medium (CM) from P. acnesprimed macrophages promoted migration of GC cells, while P. acnes only could not. We next proved that P. acnes triggers M2 polarization of macrophages via TLR4/PI3K/Akt signaling. Conclusions Together, our finding identified that P. acnes could be a possible agent for the progression of GC besides H. pylori. M2 polarization of macrophages could be promoted by P. acnes via TLR4/PI3K/Akt signaling, thus triggers the progression of GC.

Cutibacterium acnes Induces the Expression of Immunosuppressive Genes in Macrophages and is Associated with an Increase of Regulatory T-Cells in Prostate Cancer

“…These genes, CCL17 , CCL18 , and PD-L1 , are mainly expressed in M2 macrophages, indicating that C. acnes is able to polarize the macrophage into an immunosuppressive M2 phenotype with the ability to recruit Tregs ( 15 ). In line with our results, a recently published study on gastric cancer identified C. acnes as a possible cause of increased polarization of macrophages against an M2 phenotype and increased cancer progression ( 31 ). Our microscopic examination of the macrophages stimulated with C. acnes revealed a rounder shape with a foamy appearance, as previously demonstrated in M2 macrophages with PD-L1 expression ( 32 ).…”

Identification hub genes of consensus molecular subtype correlation with immune infiltration and predict prognosis in gastric cancer

“…It has been reported that ECRG4 interacted with TLR4 [ 36 ]. And TLR4/PI3K/Akt signaling was a vital way to promote M2 polarization of macrophages [ 10 ]. Our results exhibited C2orf40/ ECRG4 expression notably related to immune cell infiltration, including M2 macrophages.…”

“…Besides, the latest studies have proved that macrophages, mostly M2 polarized macrophages, have a vital role in the GC advance [ 9 , 10 ]. Infiltration of M2 macrophage might be a worthwhile biomarker for GC prognosis [ 11 ].…”

Roles of Plasmacytoid Dendritic Cells in Gastric Cancer

“…The abundance of Propionibacterium acnes is significantly increased in GC tissues and is related to TNM stages of GC patients. P. acnes induces M2 polarization of macrophages through TLR4/PI3K/Akt signaling to promote progression of GC (132). The crosstalk between macrophages and GC cells or other immune cells contributes to shaping the immunosuppressive microenvironment and to GC progression (133)(134)(135).…”