IL-8 Signaling Plays a Critical Role in the Epithelial–Mesenchymal Transition of Human Carcinoma Cells

Abstract

The switch of tumor cells from an epithelial to a mesenchymal-like phenotype (designated as epithelial-to-mesenchymal transition, EMT) is known to induce tumor cell motility and invasiveness, therefore promoting metastasis of solid carcinomas. While multiple studies have focused on elucidating the signaling events that initiate this phenotypic switch, there has been so far no characterization of the pattern of soluble mediators released by tumor cells undergoing EMT, and the potential impact that this phenotypic switch could have on the remodeling of the tumor microenvironment. Here we demonstrate that induction of EMT in human carcinoma cells via overexpression of the transcription factor Brachyury is associated with enhanced secretion of multiple cytokines, chemokines, and angiogenic factors and, in particular, with the induction of the IL-8/IL-8R axis. Our results also indicate the essential role of IL-8 signaling for the acquisition and/or maintenance of the mesenchymal and invasive features of Brachyury-overexpressing tumor cells, and demonstrate that IL-8 secreted by tumor cells undergoing EMT could potentiate tumor progression by inducing adjacent epithelial tumor cells into EMT. Altogether, our results emphasize the potential role of EMT in the modulation of the tumor microenvironment via secretion of multiple soluble mediators and suggest that IL-8 signaling blockade may provide a means of targeting mesenchymal-like, invasive tumor cells.

Chemokines in tumor development and progression

“…Overexpression of a T-box transcription factor, Brachyury, also induces EMT in human pancreatic cancer cell lines, along with enhanced expression of several chemokines, including CXCL8, CCL5, and CXCL1 [18]. The inhibition of CXCL8 signaling pathway also abrogates Brachyury-induced EMT phenotypes and invasive capacity of cells [18]. These observations suggest that several chemokines may play important roles in EMT, which is a necessary step for the malignant progression of cancer ( Figure 1).…”

“…Increasing lines of evidence indicate that EMT in cancer cells is initiated by overexpression of several transcription factors, including Twist and Snail [15]. Overexpression of a T-box transcription factor, Brachyury, also induces EMT in human pancreatic cancer cell lines, along with enhanced expression of several chemokines, including CXCL8, CCL5, and CXCL1 [18]. The inhibition of CXCL8 signaling pathway also abrogates Brachyury-induced EMT phenotypes and invasive capacity of cells [18].…”

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

“…2 Examples of such cytokines in solid tumors include transforming growth factor (TGF)-b, a well-known regulator of EMT 3,4 as well as several other cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-8 and IL-6. [5][6][7][8] Oncostatin M (OSM), a member of the IL-6 family, was originally identified as an inhibitor of melanoma cell growth in vitro. 9 It was also shown to suppress proliferation but induce mesenchymal-like differentiation of several breast cancer cell lines in vitro.…”

MiR-129-5p is down-regulated and involved in migration and invasion of gastric cancer cells by targeting interleukin-8

“…It has well demonstrated that IL-8 is involved in several types of tumor and play significant roles in tumor growth, survival, neovascularization, migration, and invasion [16][17][18]. Moreover, IL-8 is considered as a target for therapeutic intervention of cancers [26]. Increased serum levels of circulating IL-8 has been reported in GC patients than healthy controls [27,28], and IL-8 has been suggested to be associated with adhesion, migration, invasion and chemosensitivity, vascularity of GC [29][30][31].…”