Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts

Naito, Yutaka; Yamamoto, Yusuke; Sakamoto, Naoya; Shimomura, Iwao; Kogure, Akiko; Kumazaki, Minami; Yokoi, Akira; Yashiro, Masakazu; Kiyono, Tohru; Yanagihara, Kazuyoshi; Takahashi, Ryou‐u; Hirakawa, Kosei; Yasui, Wataru; Ochiya, Takahiro

doi:10.1038/s41388-019-0832-4

Cited by 95 publications

(90 citation statements)

References 46 publications

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“…Since CAFs conditioned media attracted more migrated cancer cells, there might be cytokines, chemokines or other factors contributing to invasion and metastasis of GC cells. Exosome can be taken up by neighboring or distant cells, subsequently leading to changes in gene expression, and it plays a crucial role in cancer biology with vesicular transport [21][22][23][24][25][26]. In our study, exosomal MMP11 was found overexpressed in gastric CAFs.…”

Section: Discussionsupporting

confidence: 48%

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression

Xu¹,

Zhang²,

Ye³

et al. 2019

Int. J. Biol. Sci.

127

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Solid tumors consist of various types of stromal cells in addition to cancer cells. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and play an essential role in tumor progression and metastasis in a variety of malignancies, including gastric cancer. However, the effects of CAFs on gastric cancer cells' progression and metastasis are not well studied. Here we show that matrix metalloproteinase 11 (MMP11) in exosomes secreted from CAFs can be delivered into gastric cancer cells. Gastric CAFs promote gastric cancer cell migration partially through exosomal MMP11. Moreover, MMP11 is overexpressed in exosomes purified from plasma of gastric cancer patients and tumor tissues and associated with overall survival of gastric patients. We also find that MMP11 is negatively regulated by exosomal miR-139 in the CAFs of gastric cancer. Exosomal miR-139 inhibits tumor growth and metastasis of gastric cancer cells by decreasing the expression of MMP11 in vitro and in vivo. Thus, we propose that exosomal miR-139 derived from gastric CAFs could inhibit the progression and metastasis of gastric cancer by decreasing MMP11 in tumor microenvironment.

show abstract

Section: Discussionsupporting

confidence: 48%

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression

Xu¹,

Zhang²,

Ye³

et al. 2019

Int. J. Biol. Sci.

127

View full text Add to dashboard Cite

show abstract

“…We observed a very modest difference in transcript levels of adhesion molecules upon osteosarcoma cell-derived EV stimulation, implicating that EVs do not play a direct role in endothelial cell activation in vitro. However, in the current study, we did not investigate potential indirect effects, which might include EV-regulated cytokine release from other stromal cells that can drive increased adhesion or endothelial permeability [38]. Although widely used as an experimental model in cancer biology research, our in vitro model employing immortalized established cancer cell lines has several drawbacks.…”

Section: Discussionmentioning

confidence: 99%

Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming

Mazumdar

Urdínez

Boro

et al. 2020

IJMS

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Tumor-secreted extracellular vesicles (EVs) have been identified as mediators of cancer–host intercellular communication and shown to support pre-metastatic niche formation by modulating stromal cells at future metastatic sites. While osteosarcoma, the most common primary malignant bone tumor in children and adolescents, has a high propensity for pulmonary metastases, the interaction of osteosarcoma cells with resident lung cells remains poorly understood. Here, we deliver foundational in vitro evidence that osteosarcoma cell-derived EVs drive myofibroblast/cancer-associated fibroblast differentiation. Human lung fibroblasts displayed increased invasive competence, in addition to increased α-smooth muscle actin expression and fibronectin production upon EV treatment. Furthermore, we demonstrate, through the use of transforming growth factor beta receptor 1 (TGFBR1) inhibitors and CRISPR-Cas9-mediated knockouts, that TGFβ1 present in osteosarcoma cell-derived EVs is responsible for lung fibroblast differentiation. Overall, our study highlights osteosarcoma-derived EVs as novel regulators of lung fibroblast activation and provides mechanistic insight into how osteosarcoma cells can modulate distant cells to potentially support metastatic progression.

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“…Several findings support the hypothesis that the bioactive molecules encapsulated in the EVs are capable of modifying the functions of the recipient cells. Tumor-derived EVs, also referred as oncosomes due to the fact that their cargo is composed by oncogenic macromolecules (Meehan et al, 2016), have been proven to induce changes in the phenotype of neighboring as well as distant cells, promoting tumor growth and local invasion in different cancer types (Webber et al, 2015;Fang et al, 2018;Naito et al, 2019). In addition, atypically large (1-10 µm in diameter) EVs derived from amoeboid tumor cells have been recently identified in the circulation of different mouse models of prostate cancer as well as in the biological fluids of metastatic prostate cancer patients (Di Vizio et al, 2012).…”

Section: New Horizons Of Organoids Application: Modeling Evs Releasementioning

confidence: 99%

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

Fiorini

Veghini

Corbo

2020

Front. Cell Dev. Biol.

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Homotypic and heterotypic interactions between cells are of crucial importance in multicellular organisms for the maintenance of physiological functions. Accordingly, changes in cell-to-cell communication contribute significantly to tumor development. Cancer cells engage the different components of the tumor microenvironment (TME) to support malignant proliferation, escape immune control, and favor metastatic spreading. The interaction between cancerous and non-cancerous cell types within tumors occurs in many ways, including physical contact and paracrine signaling. Furthermore, local and long-range transfer of biologically active molecules (e.g., DNA, RNA, and proteins) can be mediated by small extracellular vesicles (EVs) and this has been shown to influence many aspects of tumor progression. As it stands, there is a critical need for suitable experimental systems that enable modeling the cell-to-cell communications occurring in cancer. Given their intrinsic complexity, animal models represent the ideal system to study cell-to-cell interaction between different cell types; however, they might make difficult to assess individual contribution to a given phenotype. On the other hand, simplest experimental models (i.e., in vitro culture systems) might be of great use when weighing individual contributions to a given phenomenon, yet it is imperative that they share a considerable number of features with human cancer. Of the many culture systems available to the scientific community, patient-derived organoids already proved to faithfully recapitulate many of the traits of patients' disease, including genetic heterogeneity and response to therapy. The organoid technology offers several advantages over conventional monolayer cell cultures, including the preservation of the topology of cell-to-cell and cell-to-matrix interactions as observed in vivo. Several studies have shown that organoid cultures can be successfully used to study interaction between cancer cells and cellular components of the TME. Here, we discuss the potential of using organoids to model the interplay between cancer and non-cancer cells in order to unveil biological mechanisms involved in cancers initiation and progression, which might ultimately lead to the identification of novel intervention strategy for those diseases.

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Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts

Cited by 95 publications

References 46 publications

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression

Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

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