Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44

Abstract

Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

“…A previous study showed that IL18 directly increased the migration of gastric cancer cells through F-actin polymerization and decreased tensin levels (16). IL18 enhanced melanoma cell migration via the generation of reactive oxygen intermediates and the MAPK pathway (12), and IL18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by increasing CD44 and VEGF (15). We verified these mechanisms and confirmed that IL18 promotes tumor cell proliferation and invasion Figure 6.…”

“…IL18 secreted by microglia (which had been activated by C6 gliomaderived extracellular matrix) enhanced migration of C6 glioma (14). Endogenous IL18 was shown to facilitate gastric cancer cell immune escape by suppressing CD70 and increasing gastric cancer cell metastatic ability by upregulating CD44 and VEGF (15). IL18 also increased cell migration directly through filamentous actin (F-actin) polymerization and tensin downregulation in gastric cancer cells (16).…”

Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

“…Overall, these results suggest that IL-18 plays a key role in TSP-1 expression involving JNK (Kim et al, 2006). Endogenous IL-18 facilitate cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF (Kang et al, 2009). IL-18 show dual effects on inhibition HBV replication and promotion of metastasis and migration in human hepatocytes.…”

“…IL-18 levels suppress CD70 expression and increases immune susceptibility of cancer cells. Endogenous IL-18 facilitate cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF (Kang et al, 2009). Expression of IL-18/IL-18R were remarkably up regulates and triggered signaling pathway related to metastasis in hepatocellular carcinoma (Zang et al, 2011).…”

IL-18 Is Involved in Eosinophil-Mediated Tumoricidal Activity against a Colon Carcinoma Cell Line by Upregulating LFA-1 and ICAM-1

“…This cytokine appears to have both pro-and anti-tumor activities. On the one hand, IL-18 facilitated tumor cell immune escape by suppressing CD70, increasing metastatic potential, and promoting angiogenesis by stimulating production of CD44 and VEGF (52). On the other hand, IL-18 exerted antitumor effects by inducing an immune response to cancer cells, notably in colon cancer (20,(27)(28)(29)(30).…”