Gastric cancer‐derived exosomes facilitate pulmonary metastasis by activating ERK‐mediated immunosuppressive macrophage polarization

Abstract

Gastric cancer (GC) with pulmonary metastasis is one of the deadliest diseases in the world; however, the underlying pathological mechanisms and potential therapeutic targets remain to be elucidated. As exosomes play indispensable roles in the formation of premetastatic niches (PMN) and cancer metastasis. Therefore, investigating the underlying mechanisms of exosome-mediated pulmonary metastasis of GC may shed new light on identifying novel therapeutic targets for GC treatment. GC-derived exosomes were isolated from the conditioned medium of mouse forestomach carcinoma (MFC) cell line. The effects of MFC-derived exosomes on pulmonary macrophage polarization were analyzed by reversetranscription polymerase chain reaction and flow cytometry. Expression of PD-L1 and other proteins was evaluated by Western blot. Exosomal microRNAs (miRNAs) were analyzed by microarray. GC-derived exosomes (GC-exo) accumulated in high numbers in the lungs and were ingested by macrophages. The extracellular-signalregulated kinase (ERK) signaling pathway was activated by GC-exo, inducing macrophage immunosuppressive-phenotype differentiation and increased PD-L1 expression. miRNA-sequencing identified 130 enriched miRNAs in GC-exo. Among the enriched miRNAs, miR-92a-3p plays a major role in activating ERK signaling via inhibition of PTEN expression. In addition, inhibiting ERK signaling with PD98059 significantly reduced the expression of PD-L1 in macrophages and, therefore, reversed the immunosuppressive PMN and inhibited the colonization of GC cells in the lungs. This study identified a novel mechanism of GC-exo mediated PD-L1 expression in lung macrophages that facilitates lung PMN formation and GC pulmonary metastasis, which also provided a potential therapeutic target for GC with pulmonary metastasis treatment.

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…It was reported that tumor‑derived exosomes were able to promote the secretion of CCL1 by lung fibroblasts, which in turn resulted in differentiation of regulatory T cells (Tregs) via activating its specific receptor CCR8 and establishment of an immunologically tolerant PMN [ 274 ]. Moreover, two independent studies have uncovered that tumor-derived exosomes can induce upregulation of PD-L1 through different mechanisms to drive polarization of lung immunosuppressive macrophages, thereby promoting the formation of immunosuppressive PMN [ 275 , 276 ]. In addition to their effects on cellular components of immune microenvironment, tumor-derived exosomes were also demonstrated to activate alveolar epithelial Toll-like receptor 3 (TLR3) to recruit neutrophils, which led to formation of lung PMN [ 277 ].…”

Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment

“…High-throughput sequencing showed that miR-92a-3p was added to GC-exo and activated ERK signaling by inhibiting PTEN expression. Inhibition of ERK signaling with PD98059, a specific inhibitor, notably suppressed PD-L1 expression in macrophages and reversed the immunosuppressive impact of PMN, greatly inhibiting GC cell colonization in the lung ( 129 ).…”

The biological role of extracellular vesicles in gastric cancer metastasis

“…These EVs activated the ERK signaling pathway, induced immune-suppressive phenotypic differentiation of macrophages, increased PD-L1 expression, and promoted lung metastasis of GC. Furthermore, inhibition of the ERK signaling pathway with PD98059 significantly reduced PD-L1 expression in macrophages and inhibited the colonization of GC cells in the lungs ( Gu et al, 2023 ). EVs can promote M2 polarization of macrophages, and can also inhibit M2 polarization.…”