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      Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts

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          Abstract

          Purpose

          The present review aimed to assess the role of exosomal miRNAs in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized.

          Methods

          All relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer-associated fibroblasts, miRNA, exosomal, exosome, and similar terms.

          Results

          Recent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis.

          Conclusions

          Finding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.

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          Most cited references64

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          Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy.

          Andrea L Kasinski, Frank J Slack (2011)
          In normal cells multiple microRNAs (miRNAs) converge to maintain a proper balance of various processes, including proliferation, differentiation and cell death. miRNA dysregulation can have profound cellular consequences, especially because individual miRNAs can bind to and regulate multiple mRNAs. In cancer, the loss of tumour-suppressive miRNAs enhances the expression of target oncogenes, whereas increased expression of oncogenic miRNAs (known as oncomirs) can repress target tumour suppressor genes. This realization has resulted in a quest to understand the pathways that are regulated by these miRNAs using in vivo model systems, and to comprehend the feasibility of targeting oncogenic miRNAs and restoring tumour-suppressive miRNAs for cancer therapy. Here we discuss progress in using mouse models to understand the roles of miRNAs in cancer and the potential for manipulating miRNAs for cancer therapy as these molecules make their way towards clinical trials.
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            A microRNA DNA methylation signature for human cancer metastasis.

            Amaia Lujambio, George A. Calin, Alberto Villanueva … (2008)
            MicroRNAs (miRNAs) are small, noncoding RNAs that can contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also linked different sets of miRNAs to metastasis through either the promotion or suppression of this malignant process. Interestingly, epigenetic silencing of miRNAs with tumor suppressor features by CpG island hypermethylation is also emerging as a common hallmark of human tumors. Thus, we wondered whether there was a miRNA hypermethylation profile characteristic of human metastasis. We used a pharmacological and genomic approach to reveal this aberrant epigenetic silencing program by treating lymph node metastatic cancer cells with a DNA demethylating agent followed by hybridization to an expression microarray. Among the miRNAs that were reactivated upon drug treatment, miR-148a, miR-34b/c, and miR-9 were found to undergo specific hypermethylation-associated silencing in cancer cells compared with normal tissues. The reintroduction of miR-148a and miR-34b/c in cancer cells with epigenetic inactivation inhibited their motility, reduced tumor growth, and inhibited metastasis formation in xenograft models, with an associated down-regulation of the miRNA oncogenic target genes, such as C-MYC, E2F3, CDK6, and TGIF2. Most important, the involvement of miR-148a, miR-34b/c, and miR-9 hypermethylation in metastasis formation was also suggested in human primary malignancies (n = 207) because it was significantly associated with the appearance of lymph node metastasis. Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of human cancer metastasis.
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              MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer.

              Anirban Mitra, Marion R Zillhardt, Youjia Hua … (2012)
              Cancer-associated fibroblasts (CAF) are a major constituent of the tumor stroma, but little is known about how cancer cells transform normal fibroblasts into CAFs. microRNAs (miRNA) are small noncoding RNA molecules that negatively regulate gene expression at a posttranscriptional level. Although it is clearly established that miRNAs are deregulated in human cancers, it is not known whether miRNA expression in resident fibroblasts is affected by their interaction with cancer cells. We found that in ovarian CAFs, miR-31 and miR-214 were downregulated, whereas miR-155 was upregulated when compared with normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reversion of CAFs into normal fibroblasts. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function. The most highly upregulated chemokine, CCL5, (C-C motif ligand 5) was found to be a direct target of miR-214. These results indicate that ovarian cancer cells reprogram fibroblasts to become CAFs through the action of miRNAs. Targeting these miRNAs in stromal cells could have therapeutic benefit. The mechanism by which quiescent fibroblasts are converted into CAFs is unclear. The present study identifies a set of 3 miRNAs that reprogram normal fibroblasts to CAFs. These miRNAs may represent novel therapeutic targets in the tumor microenvironment. ©2012 AACR.
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                Author and article information

                Contributors
                Fengming Yang: yfmdoctor@163.com
                Zhiqiang Ning: nzq027@126.com
                Ling Ma: 1017782680@qq.com
                Weitao Liu: liuweitaoly@163.com
                Chuchu Shao: s_chuchu@sina.com
                Yongqian Shu: shuyongqian1998@163.com
                Hua Shen: medshenhua@126.com
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 29 August 2017
                Publication date PMC-release: 29 August 2017
                Publication date Collection: 2017
                Volume: 16
                Electronic Location Identifier: 148
                Affiliations
                [1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of Oncology, , Sir Run Run Hospital, Nanjing Medical University, ; Nanjing, China
                [2 ]Department of Oncology, The first People’s Hospital of Wujiang district, Suzhou, 215200 China
                [3 ]ISNI 0000 0004 1799 0784, GRID grid.412676.0, Department of Oncology, , The First Affiliated Hospital of Nanjing Medical University, ; 300 Guangzhou Road, Nanjing, 210029 People’s Republic of China
                [4 ]Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Shanghai, China
                [5 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of Pathology, , Nanjing Medical University, ; Nanjing, People’s Republic of China
                Article
                Publisher ID: 718
                DOI: 10.1186/s12943-017-0718-4
                PMC ID: 5576273
                PubMed ID: 28851377
                SO-VID: 17d6b03b-c507-452a-ab11-9f830af5ab47
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 1 June 2017
                Date accepted : 25 August 2017
                Funding
                Funded by: The Project of Invigorating Health Care through Science,Technology and Education(Jiangsu Provincial Medical Youth Talent QNRC2016856)
                Award ID: iangsu Provincial Medical Youth Talent QNRC2016856
                Award Recipient :
                Funded by: the National Natural Science Foundation of China
                Award ID: 81276896
                Award Recipient :
                Funded by: the Priority Academic Program Development of Jiangsu Higher Education Institutions
                Award ID: JX10231801
                Award Recipient :
                Funded by: the Natural Science Foundation of Jiangsu Province
                Award ID: No BK20171484
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer-associated fibroblasts,mirna,exosome,cancer,mechanism
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer-associated fibroblasts, mirna, exosome, cancer, mechanism

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