CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p

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Abstract

Background

Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells.

Methods

The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined.

Results

CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103 ⁺ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103 ⁺ exosomes were increased in blood samples from CCRCC patients with lung metastasis.

Conclusions

CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103 ⁺ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103 ⁺ exosomes as a potential metastatic diagnostic biomarker.

Graphical abstract

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Electronic supplementary material

The online version of this article (10.1186/s12943-019-0997-z) contains supplementary material, which is available to authorized users.

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Most cited references 17

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Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis.

Joshua Hood, Roman San, Samuel Wickline (2011)

Exosomes are naturally occurring biological nanovesicles utilized by tumors to communicate signals to local and remote cells and tissues. Melanoma exosomes can incite a proangiogenic signaling program capable of remodeling tissue matrices. In this study, we show exosome-mediated conditioning of lymph nodes and define microanatomic responses that license metastasis of melanoma cells. Homing of melanoma exosomes to sentinel lymph nodes imposes synchronized molecular signals that effect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes. Our findings highlight the pathophysiologic role and mechanisms of an exosome-mediated process of microanatomic niche preparation that facilitates lymphatic metastasis by cancer cells.

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Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance.

Nicholas Syn, Lingzhi Wang, Gautam Sethi … (2016)

Exosomes are extracellular signalosomes that facilitate eukaryotic intercellular communication under a wide range of normal physiological contexts. In malignancies, this regulatory circuit is co-opted to promote cancer cell survival and outgrowth. Tumour-derived exosomes (TDEs) carry a pro-EMT (epithelial-mesenchymal transition) programme including transforming growth factor beta (TGFβ), caveolin-1, hypoxia-inducible factor 1 alpha (HIF1α), and β-catenin that enhances the invasive and migratory capabilities of recipient cells, and contributes to stromal remodelling and premetastatic niche formation. The integrin expression patterns on TDEs appear to dictate their preferential uptake by organ-specific cells, implying a crucial role of this pathway in organotropic metastasis. Through the expression of immunomodulatory molecules such as CD39 and CD73, TDEs modify the immune contexture of the tumour microenvironment, which could have implications for immunotherapy. Hence, targeting TDE dysregulation pathways, such as the heparanase/syndecan-1 axis, could represent novel therapeutic strategies in the quest to conquer cancer.

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Herbert Riechelmann, Ira-Ida Skvortsova, Teresa Steinbichler … (2017)

Exosomes are small membrane vesicles with a size ranging from 40 to 100nm. They can serve as functional mediators in cell interaction leading to cancer metastasis. Metastasis is a complex multistep process of cancer cell invasion, survival in blood vessels, attachment to and colonization of the host organ. Exosomes influence every step of this cascade and can be targeted by oncological treatment. This review highlights the role of exosomes in the various steps of the metastatic cascade and how exosome dependent pathways can be targeted as therapeutic approach or used for liquid biopsies.

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Author and article information

Contributors

Wanhai Xu: +86-45166252986 , xuwanhai@hrbmu.edu.cn

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): 11 April 2019

Publication date PMC-release: 11 April 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 86

Affiliations

[1 ]ISNI 0000 0001 2204 9268, GRID grid.410736.7, Department of Urology (Heilongjiang Key Laboratory of Scientific Research in Urology), , the Fourth Hospital of Harbin Medical University, ; No. 37 Yi-Yuan Street, Nangang District, Harbin, Heilongjiang Province 150081 People’s Republic of China

[2 ]ISNI 0000 0004 1797 9737, GRID grid.412596.d, Department of Neurosurgery, , The First Affiliated Hospital of Harbin Medical University, ; Harbin, Heilongjiang Province People’s Republic of China

Article

Publisher ID: 997

DOI: 10.1186/s12943-019-0997-z

PMC ID: 6458839

PubMed ID: 30975145

SO-VID: 81b53fc5-9c7f-43b0-9db9-155ea2bece9f

License:

Open Access This 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 : 6 November 2018

Date accepted : 7 March 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81602225

Award ID: 81771898

Award ID: 81572482

Award Recipient : Lu Wang Guang Yang Wanhai Xu

Funded by: FundRef http://dx.doi.org/10.13039/501100010031, Postdoctoral Research Foundation of China;

Award ID: 2016M601451

Award ID: 2018M631964

Award Recipient : Lu Wang Guang Yang

Funded by: Natural Science Foundations of Heilongjiang Province

Award ID: QC2013C096

Award Recipient : Guang Yang

Funded by: FundRef http://dx.doi.org/10.13039/501100010009, Heilongjiang Provincial Postdoctoral Science Foundation;

Award ID: LBH-Z16103

Award Recipient : Lu Wang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer stem cells,mir-19b-3p,epithelial-mesenchymal transition,cd103+ exosomes,lung metastasis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer stem cells, mir-19b-3p, epithelial-mesenchymal transition, cd103+ exosomes, lung metastasis

CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p

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Abstract

Background

Methods

Results

Conclusions

Graphical abstract

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 17

Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis.

Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance.

The role of exosomes in cancer metastasis.

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