Interleukin-6 Mediates Epithelial–Stromal Interactions and Promotes Gastric Tumorigenesis

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.

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…The media collected from GC lines have induced IL‐6 secretion in fibroblasts considered as the paracrine stimulant of proliferation of tumor gastric cells through the activation of STAT3 signaling 63. Besides, the upregulation of IL‐6 after the coincubation of fibroblasts with H. pylori (cagA+vacA+), we have observed a reciprocal increase in the expression of SDF‐1 mRNA.…”

“…The expression of IL‐6 and IL‐8 mRNAs was implicated in the early stage of tumorigenesis 35, 63. The media collected from GC lines have induced IL‐6 secretion in fibroblasts considered as the paracrine stimulant of proliferation of tumor gastric cells through the activation of STAT3 signaling 63.…”

Differential Roles of ASK1 and TAK1 in Helicobacter pylori-Induced Cellular Responses

“…However, in H. pylori-infected gastric mucosa, numerous inflammatory cells migrate into the lamina propria and definitely play crucial roles in inflammation and carcinogenesis (67)(68)(69)(70)(71). Importantly, ROS and cytokine production from innate immune cells are involved in the pathogenesis of inflammatory diseases (72,73), including H. pylori infection (74)(75)(76)(77)(78).…”

Fas and TRAIL ‘death receptors’ as initiators of inflammation: Implications for cancer

“…Such factors may directly benefit the tumor by acting as autocrine growth or survival factors and much evidence has accumulated to link specific cytokines with a proliferative and pro-angiogenic role in tumor growth. Serum levels of the pleotropic cytokine IL-6 are elevated in many cancers and the role of IL-6 in promoting tumor growth has been underlined in mouse models of gastric [50], pancreatic [34,61] and lung cancer [101]. IL-6 may promote tumor cell survival through STAT3-mediated induction of anti-apoptotic Bcl-2 family proteins, while STAT-3-mediated VEGF induction has been shown to promote angiogenesis and facilitate tumor development [113].…”