Exosomes derived from endoplasmic reticulum‑stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway

Abstract

Previous studies have shown that endoplasmic reticulum (ER) stress serves an important role in shaping the immunosuppressive microenvironment by modulating resident immune cells. However, the communication between ER-stressed tumor cells and immune cells is not fully understood. Exosomes have been reported to play a vital role in intercellular communication. Therefore, in order to investigate the role of ER stress-related exosomes in liver cancer cells mediated macrophage function remodeling, immunohistochemical analysis, western-blotting immunofluorescence and cytokine bead array analyses were performed. The results demonstrated that glucose-regulated protein 78 (GRP78) expression was upregulated in human liver cancer tissue. Moreover, 69.09% of GRP78-positive liver cancer tissues possessed macrophages expressing CD68 + (r=0.55; P<0.001). In addition to these CD68 + macrophages, interleukin (IL)-10 and IL-6 expression levels were increased in liver cancer tissues. It was also demonstrated that exosomes released by ER-stressed HepG2 cells significantly enhanced the expression levels of several cytokines, including IL-6, monocyte chemotactic protein-1, IL-10 and tumor necrosis factor-α in macrophages. Furthermore, incubation of cells with ER stress-associated exosomes resulted inactivation of the Janus kinase 2/STAT3 pathway, and inhibition of STAT3 using S3I-201 in RAW264.7 cells significantly reduced cytokine production. Collectively, the present study identified a novel function of ER stress-associated exosomes in mediating macrophage cytokine secretion in the liver cancer microenvironment, and also indicated the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway.

<p>Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications</p>

“…Almost all types of normal cells can produce exosomes, like human umbilical vein endothelial cells, mesenchymal stem cells (MSC), T cells, B cells, macrophages, dendritic cells (DC), natural killer (NK) cells. [19][20][21][22] For example, mesenchymal stem cells (MSCS) are pluripotent stem cells capable of self-renewal and multidirectional differentiation. MSCs can not only adapt to the tumor microenvironment, but also have powerful paracrine activity and secrete a large number of exosomes.…”

Exosomes as mediators of immune regulation and immunotherapy in cancer

“…Endoplasmic reticulum (ER) stress can impede the development of antitumor immune responses through reprogramming of several immune cell populations [116,117]. In macrophages, exosomes derived from liver cancer cells undergoing ER stress promoted the secretion of IL-6, MCP-1, IL-10, and TNF-a through STAT3 signaling [118]. Another study has shown that exosomal miR-27a-3p released from breast cancer cells undergoing ER stress promoted immune evasion through up-regulation of PD-L1 expression in macrophages [119].…”

A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes

“…ER stress-associated exosomes mediate macrophage cytokine secretion in the liver cancer microenvironment, and also indicate the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway. 128 Mesenchymal stem cell-derived exosomal miR-223 protects neuronal cells from apoptosis, enhances cell migration and increases miR-223 by targeting PTEN, thus activating the PI3K/Akt pathway. In addition, exosomes isolated from the serum of AD patients promote cell apoptosis through the PTEN-PI3K/Akt pathway and these studies indicate a potential therapeutic approach for AD.…”