Abstract
Gastric cancer (GC) is one of the most prevalent digestive malignancies. A great number of patients at first visit or post curative resections are diagnosed with widespread metastasis within the peritoneal cavity. Overwhelming evidence has demonstrated that exosomes, a variety of biologically functional extracellular vesicles comprising active factors, mediate the progression and metastasis of GC. Although the regulatory mechanisms of exosomes remain fairly elusive, they are responsible for intercellular communication between tumor cells and normal stroma, cancer-related fibroblasts, immune cells within the primary tumor and metastatic niche. In this review, we provide new insight into the molecular signatures of GC-associated exosomes in reprogramming the tumor microenvironment and the subsequent promotion of peritoneal metastasis—including infiltration of the gastric wall, implantation of tumor cells onto the pre-metastatic peritoneum, and remodeling of the pre-metastatic niche. Based on this review, we hope to draw a more general conclusion for the functions of exosomes in the progression and peritoneal metastasis of GC and highlight the future perspective on strategies targeting exosomes in prognostic biomarkers and therapy for peritoneal metastasis.
Highlights
Gastric cancer (GC) is the fifth most lethal malignancies worldwide and the third dominating cause of cancer-related death, responsible for 7% of cancer cases and 9% of the deaths [1], especially in East Asia, such as Japan, Korea, and China [2]
Exosomes participate in pluripotent cell functions in peritoneal metastases (PM), inducing cancer-associated fibroblasts (CAFs), epithelial– mesenchymal transition (EMT) of cancer cells, mesothelial-tomesenchymal transition (MMT) of peritoneal cells, angiogenesis, and immune suppression, changing the environment in both local and pre-metastatic stroma [13, 14]
This study indicated that exosomes secreted by secondary metastatic lesions rather than primary cancer mass are more inclined to promote proliferation and invasion
Summary
Gastric cancer (GC) is the fifth most lethal malignancies worldwide and the third dominating cause of cancer-related death, responsible for 7% of cancer cases and 9% of the deaths [1], especially in East Asia, such as Japan, Korea, and China [2]. Extensive studies have validated that exosomes contribute to different aspects of GC progression and PM by promoting primary tumor cells growth, invasion, and remodeling the peritoneal microenvironment to make it suitable for metastatic niches [11, 12]. Exosomes derived from GC could deliver functional elements to induce CAF formation by activating AKT, ERK, and TGF-b/Smad signaling pathway, which are consistent with the studies of other cancers [53, 54].
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