Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial–stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6–positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6−/−) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6−/− mice, compared with WT mice. Impaired tumor development in IL-6−/− mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3–related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell–conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
Highlights
Gastric cancer is a leading cause of cancer-related death [1]
Stromal Fibroblasts Express IL-6 in Gastric Cancer To explore the involvement of IL-6 in gastric carcinogenesis, we performed an immunohistochemical analysis of IL-6 in 5 cases of Helicobacter pylori–negative healthy control, 5 cases of Helicobacter pylori–positive gastritis, 5 cases of gastric adenoma, and 31 cases of gastric cancer
We demonstrated that IL-6 plays an important role in the epithelial–stromal interaction in gastric tumorigenesis
Summary
Gastric cancer is a leading cause of cancer-related death [1]. The global incidence of gastric cancer was estimated to be 934,000 cases in 2002; 56% of new cases occurred in East Asia, 11% of which were in Japan [2]. Despite recent advances in combination chemotherapies [3], the outcome of unresectable gastric cancer remains poor, and new treatments, including molecularly targeted therapies, are urgently needed. Mutations and amplifications of certain kinases have been reported to be associated with human gastric carcinogenesis [4]. Trastuzumab, a monoclonal antibody that acts on the HER2/neu (erbB2) receptor, is currently the only molecularly targeted drug that is used against gastric cancer [5]. Interleukin-6 (IL-6) is a pleiotropic cytokine involved in tumor initiation, promotion, and progression [6]. IL-6 has been reported to influence invasiveness and metastasis in various experimental models, suggesting its involvement in cancer progression [11,12,13,14,15]
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