The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

Abstract

Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…CAFs release a significant amount of galectin-1, which promotes EMT and gastric cancer progression by binding to β1 integrin [260]. EMT is also promoted by CAFs-derived IL-33 through the activation of the ERK1/2-SP1-ZEB2 pathway [261].…”

Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

“…On the other hand, CAFs can enhance the metastatic potential of cancer cells by the induction of EMT, through the paracrine secretion of transforming growth factor-β (TGF-β),which promotes cancer cell invasion [ 88 , 89 ] and the differentiation of CAFs in an autocrine fashion [ 90 ], CXCL12 [ 91 ], interleukin 6 (IL-6) [ 92 , 93 ], or matrix metalloproteinases (MMPs) [ 94 ]. CAF-induced EMT is also shown in experimental settings using conditioned media and co-cultures [ 95 , 96 , 97 , 98 ]. In addition, TGF-β together with some chemokines and cytokines such as IL-6 and CXCL9 promote cancer progression by suppressing the antitumor immune response leading to the disruption of T cell function and cancer cell immune evasion [ 99 , 100 ].…”

Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis

“…The cell-to-cell interaction between CAFs and the tumor cells and other surrounding cells including cancer-associated macrophages (CAMs) is essential [112]. In a recent study, CAFs-derived interleukin-33 (IL-33) has been found to mediate the activation of the ERK1/2-SP1-ZEB2 pathway through its receptor ST2L [113]. The secretion of IL-33 by CAFs can be stimulated by TNF-α released by the surrounding GC cells.…”