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Background: Increasing evidence has demonstrated that mesenchymal stem cells (MSCs) play a role in the construction of tumor microenvironments. Co-culture between tumor cells and MSCs provides an easy and useful platform for mimicking tumor microenvironments and identifying the important members involved in tumor progress. The long non-coding RNAs (lncRNAs) have been shown to regulate different tumorigenic processes. In this study, we aimed to examine functional lncRNA deregulations associated with breast cancer malignancy instigated by MSC-MCF-7 co-culture., Methods: The microarrays were used to profile the expression changes of lncRNAs in MCF-7 cells during epithelial-mesenchymal transition (EMT) induced by co-culture with MSCs. We found that an intergenic lncRNA KB-1732A1.1 (termed LincK, partly overlapped with GASL1) was significantly elevated. To investigate the biological function of LincK, the expression of EMT markers, cell migration, invasion, proliferation, and colony formation were evaluated in vitro and xenograft assay in nude mice were performed in vivo. Furthermore, we detected LincK expression in clinical samples using RNAscope® technology and verified aberrant expression of LincK in breast cancer data sets from The Cancer Genome Atlas (TCGA) by bioinformatic analysis. The underlying mechanisms of LincK were investigated using mRNA microarray analyses, Western blot, RNA pull down, and RNA immunoprecipitation., Results: LincK induced an EMT progress in breast cancer cells (BCC) MCF-7, MDA-MB-453, and MDA-MB-231. The depletion of LincK decreased the growth, migration, and invasion in BCC, whereas the overexpression of LincK exerted the opposite effects. Moreover, knockdown of LincK repressed tumorigenesis, and ectopic expression of LincK promoted tumor growth in MCF-7 xenograft model. LincK ablation in MDA-MB-231 cells dramatically impaired lung metastasis when incubated intravenously into nude mice. Further, LincK was frequently elevated in breast cancer compared with normal breast tissue in clinical samples. Mechanistically, LincK may share common miRNA response elements with PBK and ZEB1 and regulate the effects of miR-200 s., Conclusion: LincK plays a significant role in regulating EMT and tumor growth and could be a potential therapeutic target in breast cancer.

Background: The initiation and progression of hepatocellular carcinoma (HCC) are largely dependent on its local microenvironment. Adipocytes are an important component of hepatic microenvironment in nonalcoholic fatty liver disease (NAFLD), which is a significant risk factor for HCC. Given the global prevalence of NAFLD, a better understanding of the interplay between HCC cells and adipocytes is urgently needed. Exosomes, released by malignant cells, represent a novel way of cell-cell interaction and have been shown to play an important role in cancer cell communication with their microenvironment. Here, we explore the role of HCC-derived exosomes in the cellular and molecular conversion of adipocytes into tumor-promoting cells., Methods: Exosomes were isolated from HCC cell line HepG2 and added to adipocytes. Transcriptomic alterations of exosome-stimulated adipocytes were analyzed using gene expression profiling, and secretion of inflammation-associated cytokines was detected by RT-PCR and ELISA. In vivo mouse xenograft model was used to evaluate the growth-promoting and angiogenesis-enhancing effects of exosome-treated adipocytes. Protein content of tumor exosomes was analyzed by mass spectrometry. Activated phospho-kinases involved in exosome-treated adipocytes were detected by phospho-kinase antibody array and Western blot., Results: Our results demonstrated that HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes. The tumor exosome-treated adipocytes, named exo-adipocytes, promoted tumor growth, enhanced angiogenesis, and recruited more macrophages in mouse xenograft model. In vitro, conditioned medium from exo-adipocytes promoted HepG2 cell migration and increased tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, we found HepG2 exosomes activated several phopho-kinases and NF-κB signaling pathway in exo-adipocytes. Additionally, a total of 1428 proteins were identified in HepG2 exosomes by mass spectrometry., Conclusions: Our results provide new insights into the concept that tumor cell-derived exosomes can educate surrounding adipocytes to create a favorable microenvironment for tumor progression.

Background: In 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., Methods: Exosomes 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., Results: Data 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., Conclusions: Our 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.

Tumor behavior is not entirely determined by tumor cells. Studies have demonstrated that a variety of non-tumor cells in the tumor microenvironment affect tumor behavior; thus, a new focus of cancer research has been the development of novel cancer treatment ideas and therapeutic targets based on the effects of these cells. Mesenchymal stem cells (MSCs) are an important component of the tumor microenvironment; however, previous studies have produced controversial results regarding whether MSCs promote or inhibit tumor growth and progression. In particular, Naïve MSCs and tumor-derived MSCs (T-MSCs) have different functions. Naïve MSCs could exert bidirectional effects on tumors because these cells can both promote and inhibit tumor progression while T-MSCs promote tumor progression due to influences from the tumor itself and from the inflammatory tumor microenvironment. As an unhealed wound, tumor produces a continuous source of inflammatory mediators and causes aggregation of numerous inflammatory cells, which constitute an inflammatory microenvironment. Inflammatory factors can induce homing of circulating MSCs and MSCs in adjacent tissues into tumors, which are then being "educated" by the tumor microenvironment to support tumor growth. T-MSCs could recruit more immune cells into the tumor microenvironment, increase the proportion of cancer stem cells and promote tumor angiogenesis, further supporting tumor progression. However, as plasticity is a fundamental feature of MSCs, MSCs can also inhibit tumors by activating various MSC-based signaling pathways. Studies of the mechanisms by which interactions among tumors, MSCs, and the inflammatory microenvironment occur and methods to disrupt these interactions will likely reveal new targets for cancer therapy.

Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside.