Tumor Mesenchymal Stromal Cells Regulate Cell Migration of Atypical Teratoid Rhabdoid Tumor through Exosome-Mediated miR155/SMARCA4 Pathway

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Abstract

Atypical teratoid/rhabdoid tumor (ATRT) is a rare pediatric brain tumor with extremely high aggressiveness and poor prognosis. The tumor microenvironment is regulated by a complex interaction among distinct cell types, yet the crosstalk between tumor-associated mesenchymal stem cells (tMSCs) and naïve ATRT cells are unclear. In this study, we sought to identify the secretory factor(s) that is responsible for the tMSC-mediated regulation of ATRT migration. Comparing with ATRT cell alone, co-culture of tMSCs or addition of its conditioned medium (tMSC-CM) promoted the migration of ATRT, and this effect could be abrogated by exosome release inhibitor GW4869. The exosomes in tMSC-CM were detected by transmission electron microscope and flow cytometry. ATRT naïve cell-derived conditioned media (ATRT-CM) also enhanced the exosome secretion from tMSCs, indicating the interplay between ATRT cells and tMSCs. Microarray analysis revealed that, compared with that in bone marrow-derived MSCs, microRNA155 is the most upregulated microRNA in the tMSC-CM. Tracing the PK67-labeled exosomes secreted from tMSCs confirmed their incorporation into naïve ATRT cells. After entering ATRT cells, miR155 promoted ATRT cell migration by directly targeting SMARCA4. Knockdown of SMARCA4 mimicked the miR155-driven ATRT cell migration, whereas SMARCA4 overexpression or the delivery of exosomes with miR155 knockdown suppressed the migration. Furthermore, abrogation of exosome release with GW4869 reduced the tumorigenesis of the xenograft containing naïve ATRT cells and tMSCs in immunocompromised recipients. In conclusion, our data have demonstrated that tMSCs secreted miR155-enriched exosomes, and the exosome incorporation and miR155 delivery further promoted migration in ATRT cells via a SMARCA4-dependent mechanism.

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Tumor-associated stromal cells as key contributors to the tumor microenvironment

Karen M. Bussard, Lysette Mutkus, Kristina Stumpf … (2016)

The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.

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Exosome-mediated breast cancer chemoresistance via miR-155 transfer

Juliana Santos, Natália Lima, Luis Sarian … (2018)

Breast cancer remains the most prevalent cause of cancer mortality in woman worldwide due to the metastatic process and therapy resistance. Resistance against cancer therapy is partially attributed to cancer stem cells (CSCs). These cells arise from epithelial cells undergoing epithelial-to-mesenchymal transition (EMT) and might be responsible for tumor recurrence. In this study, we reported the relevance of miR-155 upregulation in chemoresistant cells associated with EMT. Notably, we found miR-155 induction in exosomes isolated from CSCs and resistant cells, followed by resistant cells’ exosome transfer to the recipient sensitive cells. Functionally, miR-155 mimic assay showed an enrichment in miR-155 from exosome concomitant with miR-155 exosome transfer to breast cancer cells. In parallel to these effects, we also observed EMT change in miR-155 transfected cells. The chemoresistance phenotype transfer to sensitive cells and the migration capability was analyzed by MTT and scratch assays and our results suggest that exosomes may intermediate resistance and migration capacity to sensitive cells partly through exosome transfer of miR-155. Taken together, our findings establish the significance of exosome-mediate miR-155 chemoresistance in breast cancer cells, with implications for targeting miR-155 signaling as a possible therapeutic strategy.

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Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells: Influence in Cancer Development

Federica Papaccio, Francesca Paino, Tarik Regad … (2017)

Abstract Tumors are composed of different types of cancer cells that contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) play an important role in cancer initiation and progression. Like their stem cells counterpart, CSCs are also characterized by self‐renewal and the capacity to differentiate. A particular population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into cells of mesodermal characteristics. Several studies have reported the potential pro‐or anti‐tumorigenic influence of MSCs on tumor initiation and progression. In fact, MSCs are recruited to the site of wound healing to repair damaged tissues, an event that is also associated with tumorigenesis. In other cases, resident or migrating MSCs can favor tumor angiogenesis and increase tumor aggressiveness. This interplay between MSCs and cancer cells is fundamental for cancerogenesis, progression, and metastasis. Therefore, an interesting topic is the relationship between cancer cells, CSCs, and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of normal and CSCs in cancer development. The understanding of the role of MSCs in cancer is also important in cancer management. Stem Cells Translational Medicine 2017;6:2115–2125

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 24 May 2019

Publication date Collection: May 2019

Volume: 11

Issue: 5

Electronic Location Identifier: 720

Affiliations

[1 ]Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan; molly0103@ 123456gmail.com (Y.-P.Y.); g39005005@ 123456gmail.com (Y.C.); yarmishyn@ 123456gmail.com (A.A.Y.)

[2 ]School of Pharmaceutical Science, National Yang Ming University, Taipei 112, Taiwan

[3 ]School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; nguyennhi204@ 123456hotmail.com (P.N.N.N.); keyw4928067@ 123456gmail.com (W.-J.H.); chenyw@ 123456vghtpe.gov.tw (Y.-W.C.); pihuang@ 123456vghtpe.gov.tw (P.-I.H.); yylee62@ 123456gmail.com (Y.-Y.L.); mtchen@ 123456vghtpe.gov.tw (M.-T.C.)

[4 ]Cancer Center, Taipei Veterans General Hospital, Taipei 112, Taiwan

[5 ]Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan; uf004693@ 123456mail2000.com.tw

[6 ]Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan

[7 ]Division of Oral and Maxillofacial Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; wllo@ 123456vghtpe.gov.tw

[8 ]Department of Dentistry and Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan

[9 ]Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; wangcy@ 123456vghtpe.gov.tw (C.-Y.W.); yyliu@ 123456vghtpe.gov.tw (Y.-Y.L.)

[10 ]Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan

[11 ]Chest Department, Taipei Veterans General Hospital, Taipei 112, Taiwan

[12 ]Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital & National Yang-Ming University, Taipei 112, Taiwan

[13 ]Department of Neurosurgery, Shuang-Ho Hospital, New Taipei City 235, Taiwan; m513092004@ 123456tmu.edu.tw

[14 ]Taipei Neuroscience Institute, Taipei Medical University, Taipei City 110, Taiwan

[15 ]Institute of Food Safety and Health Risk Assessment, National Yang Ming University, Taipei 112, Taiwan

Author notes

[* ]Correspondence: monglien@ 123456gmail.com ; Tel.: +886-2-28757394

[†]

These authors contributed equally.

Article

Publisher ID: cancers-11-00720

DOI: 10.3390/cancers11050720

PMC ID: 6563126

PubMed ID: 31137686

SO-VID: 08e9bb3d-b131-4d95-9ac5-a04abda10512

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Tumor Mesenchymal Stromal Cells Regulate Cell Migration of Atypical Teratoid Rhabdoid Tumor through Exosome-Mediated miR155/SMARCA4 Pathway

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Most cited references 39

Tumor-associated stromal cells as key contributors to the tumor microenvironment

Exosome-mediated breast cancer chemoresistance via miR-155 transfer

Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells: Influence in Cancer Development

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