Dr. Weeks’ Comment: The cancer treatment of the future will be a “centisble” (safe and effective and cost-effective) anti-inflammatory agent in order to stop the pro-inflammatory cytokine IL-8 from spreading cancer.
“….Interleukin 8 (IL-8, CXCL8), a proinflammatory CXC chemokine, constitutes an example of a soluble mediator released by tumor cells that simultaneously function in an autocrine and paracrine mode within the tumor microenvironment. In melanoma, tumor-derived IL-8 has been shown to promote tumor cell proliferation, survival, and migration via its autocrine activity, while inducing an angiogenic response in endothelial cells and the recruitment of neutrophils to the tumor site via its paracrine activity …”
SOUL is the most “centisble” anti-inflammatory option available today.
IL-8 Signaling Plays a Critical Role in the Epithelial–Mesenchymal Transition of Human Carcinoma Cells
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. Although 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 show 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 interleukin 8 (IL-8) signaling for the acquisition and/or maintenance of the mesenchymal and invasive features of Brachyury-overexpressing tumor cells and show 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. Cancer Res; 71(15); 5296–306. ©2011 AACR.
Multiple cytokines, chemokines, and growth factors play a critical role as mediators of paracrine signals between the tumor and various components of the tumor microenvironment, which will ultimately lead to tumor growth, survival, and progression (1–3). These soluble mediators could be secreted either by the tumor cells themselves or by any of the various cellular components of the tumor microenvironment, including cancer-associated fibroblasts, immune cells, and endothelial cells, among others (4, 5). In particular, tumor-derived soluble factors have been shown to function in a paracrine fashion to reprogram the normal stroma to a tumorigenic stroma (6), as well as to work in an autocrine way promoting tumor growth, survival, and acquisition of metastatic potential (7). Interleukin 8 (IL-8, CXCL8), a proinflammatory CXC chemokine, constitutes an example of a soluble mediator released by tumor cells that simultaneously function in an autocrine and paracrine mode within the tumor microenvironment. In melanoma, tumor-derived IL-8 has been shown to promote tumor cell proliferation, survival, and migration via its autocrine activity, while inducing an angiogenic response in endothelial cells and the recruitment of neutrophils to the tumor site via its paracrine activity (8, 9).
In recent years, the importance of an epithelial–mesenchymal phenotypic switch of tumor cells [epithelial–mesenchymal transition (EMT)] has been shown during the progression of carcinomas (10, 11). The role of multiple growth factors, cytokines, and components of the extracellular matrix (ECM) in inducing EMT in epithelial tumor cells has been well documented and, for example, TGF-β, fibroblast growth factor (FGF), and TNF-α have all been implicated in the induction of EMT (10, 12–14). To date, however, there has been no comprehensive analysis of the pattern of soluble factors released by tumor cells undergoing a switch from an epithelial to a mesenchymal-like phenotype along the course of carcinoma progression. The characterization of the “secretory phenotype” of tumor cells undergoing EMT might help to understand the potential impact that this phenotypic switch could have on the remodeling of the tumor microenvironment, therefore favoring tumor progression.
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