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Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment.

ABSTRACT: Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play a key role in promoting tumor progression. The tumor uses exosomes to co-opt MSCs and re-program their functional profile from normally trophic to pro-tumorigenic. These tumor-derived small vesicles called "TEX" carry and deliver a cargo rich in proteins and nucleic acids to MSCs. Upon interactions with surface receptors on MSCs and uptake of the exosome cargo by MSCs, molecular, transcriptional and translational changes occur that convert MSCs into producers of factors that are necessary for tumor growth and that also alter functions of non-tumor cells in the TME. The MSCs re-programmed by TEX become avid producers of their own exosomes that carry and deliver mRNA and miRNA species as well as molecular signals not only back to tumor cells, directly enhancing their growth, but also horizontally to fibroblasts, endothelial cells and immune cells in the TME, indirectly enhancing their pro-tumor functions. TEX-driven cross-talk of MSCs with immune cells blocks their anti-tumor activity and/or converts them into suppressor cells. MSCs re-programmed by TEX mediate pro-angiogenic activity and convert stromal cells into cancer-associated fibroblasts (CAFs). Although MSCs have a potential to exert anti-tumor activities, they largely provide service to the tumor using the multidirectional communication system established by exosomes in the TME. Future therapeutic options consider disruption of this complex vicious cycle by either molecular or gene-regulated silencing of pro-tumor effects mediated by MSCs in the TME.

SUBMITTER: Whiteside TL

PROVIDER: S-EPMC5866206 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment.

Whiteside Theresa L TL

Seminars in immunology 20171227

Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play a key role in promoting tumor progression. The tumor uses exosomes to co-opt MSCs and re-program their functional profile from normally trophic to pro-tumorigenic. These tumor-derived small vesicles called "TEX" carry and deliver a cargo rich in proteins and nucleic acids to MSCs. Upon interactions with surface receptors on MSCs and uptake of the exosome cargo by MSCs, molecular, transcriptional and ...[more]

PMID: 29289420

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Project description:The host immune system (T-lymphocytes and their pro-inflammatory cytokines) has been shown to compromise bone regeneration ability of mesenchymal stem cells (MSCs). We have recently shown that hydrogel, used as an encapsulating biomaterial affects the cross-talk among host immune cells and MSCs. However, the role of hydrogel elasticity and porosity in regulation of cross-talk between dental-derived MSCs and immune cells is unclear. In this study, we demonstrate that the modulus of elasticity and porosity of the scaffold influence T-lymphocyte-dental MSC interplay by regulating the penetration of inflammatory T cells and their cytokines. Moreover, we demonstrated that alginate hydrogels with different elasticity and microporous structure can regulate the viability and determine the fate of the encapsulated MSCs through modulation of NF-kB pathway. Our in vivo data show that alginate hydrogels with smaller pores and higher elasticity could prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascades, leading to higher amounts of ectopic bone regeneration. Additionally, dental-derived MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. Taken together, our findings demonstrate that the mechanical characteristics and microarchitecture of the microenvironment encapsulating MSCs, in addition to presence of T-lymphocytes and their pro-inflammatory cytokines, affect the fate of encapsulated dental-derived MSCs. STATEMENT OF SIGNIFICANCE:In this study, we demonstrate that alginate hydrogel regulates the viability and the fate of the encapsulated dental-derived MSCs through modulation of NF-kB pathway. Alginate hydrogels with smaller pores and higher elasticity prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascade, leading to higher amounts of ectopic bone regeneration. MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. These findings confirm that the fate of encapsulated MSCs are affected by the stiffness and microarchitecture of the encapsulating hydrogel biomaterial, as well as presence of T-lymphocytes/pro-inflammatory cytokines providing evidence concerning material science, stem cell biology, the molecular mechanism of dental-derived MSC-associated therapies, and the potential clinical therapeutic impact of MSCs.

Project description:The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6R?) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6R? antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6R? overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6R? and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. ©2018 AACR.

Dataset Information

Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment.

Publications

Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment.

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