A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression

Abstract

Background Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood. Methods Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment. Results Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient’s pessimistic outcome. Conclusion Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.

Predicting the Recurrence of Gastric Cancer Using the Textural Features of Perigastric Adipose Tissue on [18F]FDG PET/CT

“…Macrophages are the most abundant immune cells in the tumor microenvironment [ 29 ]. The majority of macrophages in peritumoral AT are M2 macrophages, which exhibit high levels of CD163 expression [ 8 , 29 ]. M2 macrophages are known to promote progression and metastasis of gastric cancer cells [ 29 , 30 ].…”

Relationship of FDG PET/CT Textural Features with the Tumor Microenvironment and Recurrence Risks in Patients with Advanced Gastric Cancers

“…CD8 T cells and macrophages are the major immune cells in the tumor microenvironment of gastric cancer [ 35 ]. Macrophages in the tumor microenvironment predominantly exhibit an M2 phenotype with high CD163 expression [ 36 , 37 ]. M2 macrophages play a crucial role in promoting gastric cancer progression and metastasis and suppressing immune reactions in the tumor microenvironment, revealing a poor prognosis in tumors with increased M2 macrophage infiltration [ 10 , 37 ].…”

“…Macrophages in the tumor microenvironment predominantly exhibit an M2 phenotype with high CD163 expression [ 36 , 37 ]. M2 macrophages play a crucial role in promoting gastric cancer progression and metastasis and suppressing immune reactions in the tumor microenvironment, revealing a poor prognosis in tumors with increased M2 macrophage infiltration [ 10 , 37 ]. CD8 T lymphocytes are considered to perform important functions in anti-tumor reactions, and several studies have shown an improved prognosis in gastric cancers with a high density of CD8 T lymphocytes [ 10 , 38 ].…”

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

“…IL-8 (also known as CXCL8) is mainly produced by macrophages and plays a controversial role in regulating cancer progression [ 144 ]. Hypoxia increases IL-8 secretion significantly in macrophages but only slightly in gastric cancer (GC) cells [ 94 ]. Macrophage-derived CXCL8 induced by hypoxia can activate the JAK/STAT1 signaling pathway through binding to CXCR1/2 expressed on GC cells, leading to GC invasion and proliferation.…”

“…The activation of STAT1 directly upregulates the expression of IL-10, stimulating M2 polarization of macrophages through the NF-κB signaling pathway. CXCL8 production is further encouraged by NF-κB activation [ 94 ].…”