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.
Mesenchymal stem cells (MSCs) differentiate along various lineages to specialized mesodermal cells and also transdifferentiate into cells such as ectodermal neurons. MSCs are among the leading adult stem cells for application in regenerative medicine. Advantages include their immune‐suppressive properties and reduced ethical concerns. MSCs also show immune‐enhancing functions. Major histocompatibility complex II (MHC‐II) is expected to be downregulated in MSCs during neurogenesis. Ideally, “off the shelf” MSCs would be suited for rapid delivery into patients. The question is whether these MSC‐derived neurons can reexpress MHC‐II in a milieu of inflammation. Western analyses demonstrated gradual decrease in MHC‐II during neurogenesis, which correlated with the expression of nuclear CIITA, the master regulator of MHC‐II expression. MHC‐II expression was reversed by exogenous IFNY. One‐way mixed lymphocyte reaction with partly differentiated neurons showed a stimulatory effect, which was partly explained by the release of the proinflammatory neurotransmitter substance P (SP), cytokines, and decreases in miR‐130a and miR‐206. The anti‐inflammatory neurotransmitters VIP and CGRP were decreased at the peak time of immune stimulation. In summary, MSC‐derived neurons show decreased MHC‐II expression, which could be reexpressed by IFNY. The release of neurotransmitters could be involved in initiating inflammation, underscoring the relevance of immune responses as consideration for stem cell therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.