Abstract
BackgroundIn tumor microenvironment, a continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression. Accumulating evidence suggests that exosomes, a novel way of cell communication, play an important role in such cross-talk. Exosomes could facilitate the direct intercellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells. Since mesenchymal stem cells (MSCs) can be attracted to tumor sites and become an important component of the tumor microenvironment, there is an urgent need to reveal the effect of tumor exosomes on MSCs and to further explore the underlying molecular mechanisms.MethodsExosomes were harvested from lung cancer cell line A549 and added to MSCs. Secretion of inflammation-associated cytokines in exosome-treated MSCs were analyzed by RT-PCR and ELISA. The growth-promoting effect of exosome-treated MSCs on lung tumor cells was evaluated by in vivo mouse xenograft model. Signaling pathway involved in exosomes-treated MSCs was detected by PCR array of human toll-like receptor signaling pathway, RT-PCR, and Western blot.ResultsData showed that lung tumor cell A549-derived exosomes could induce a pro-inflammatory phenotype in MSCs named P-MSCs, which have significantly elevated secretion of IL-6, IL-8, and MCP-1. P-MSCs possess a greatly enhanced ability in promoting lung tumor growth in mouse xenograft model. Analysis of the signaling pathways in P-MSCs revealed a fast triggering of NF-κB. Genetic ablation of Toll-like receptor 2 (TLR2) by siRNA and TLR2-neutralizing antibody could block NF-κB activation by exosomes. We further found that Hsp70 present on the surface of lung tumor exosomes contributed to the induction of P-MSCs by A549 exosomes.ConclusionsOur studies suggest a novel mechanism by which lung tumor cell-derived exosomes induce pro-inflammatory activity of MSCs which in turn get tumor supportive characteristics.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0269-y) contains supplementary material, which is available to authorized users.
Highlights
In tumor microenvironment, a continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression
Since exosomes could be labeled by lipophilic cell tracking dyes, DiO-labeled exosomes were added to mesenchymal stem cells (MSCs) serum-free culture medium
NFκB signaling pathway is strikingly activated in pro-inflammatory MSCs (P-MSC) To further investigate the signaling pathways involved in induction of PMSCs by A549 exosomes, we focused on toll-like receptor (TLR) pathway as it has been reported to be closely related to inflammation
Summary
A continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression. Exosomes could facilitate the direct intercellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells. Tumor cells can modulate tumor stromal cells through intercellular communications. This process can be mediated through direct cell contact or through secreted signaling factors (cytokines, chemokines, and growth factors) and microvesicles. Exosomes in tumor microenvironment are attracting more and more attention. They are shown to be small particles but big players in cancer progression and metastasis [6,7,8] as cancer cells could reprogram surrounding stromal cells into tumor supportive myofibroblasts through secreted exosomes. Exosomes released by chronic lymphocytic leukemia cells could induce the transition of stromal cells into cancer-associated fibroblasts [12]
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