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Thyroid cancer stem-like cell exosomes: regulation of EMT via transfer of lncRNAs

Laboratory Investigationvolume 98pages11331142 (2018) | Download Citation

Abstract

Thyroid cancers are the most common endocrine malignancy and approximately 2% of thyroid cancers are anaplastic thyroid carcinoma (ATC), one of the most lethal and treatment resistant human cancers. Cancer stem-like cells (CSCs) may initiate tumorigenesis, induce resistance to chemotherapy and radiation therapy, have multipotent capability and may be responsible for recurrent and metastatic disease. The production of CSCs has been linked to epithelial-mesenchymal transition (EMT) and the acquisition of stemness. Exosomes are small (30–150 nm) membranous vesicles secreted by most cells that play a significant role in cell-to-cell communication. Many non-coding RNAs (ncRNA), such as long-non-coding RNAs (lncRNA), can initiate tumorigenesis and the EMT process. Exosomes carry ncRNAs to local and distant cell populations. This study examines secreted exosomes from two in vitro cell culture models; an EMT model and a CSC model. The EMT was induced in a papillary thyroid carcinoma (PTC) cell line by TGFβ1 treatment. Exosomes from this model were isolated and cultured with naïve PTC cells and examined for EMT induction. In the CSC model, exosomes were isolated from a CSC clonal line, cultured with a normal thyroid cell line and examined for EMT induction. The EMT exosomes transferred the lncRNA MALAT1 and EMT effectors SLUG and SOX2; however, EMT was not induced in this model. The exosomes from the CSC model also transferred the lncRNA MALAT1 and the transcription factors SLUG and SOX2 but additionally transferred linc-ROR and induced EMT in the normal thyroid cells. Preliminary siRNA studies directed towards linc-ROR reduced invasion. We hypothesize that CSC exosomes transfer lncRNAs, importantly linc-ROR, to induce EMT and inculcate the local tumor microenvironment and the distant metastatic niche. Therapies directed towards CSCs, their exosomes and/or the lncRNAs they carry may reduce a tumor’s metastatic capacity.

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Acknowledgements

We kindly thank Dr. John A. Copland III (Mayo Clinic, Jacksonville, FL) for the THJ-16T cell line, Dr. Daniel T. Ruan (Brigham and Women’s Hospital, Boston, MA) for the TPC-1 cell line and the staffs of the Flow Cytometry and the 3P laboratories (University of Wisconsin Carbone Cancer Center, Cancer Center Support Grant P30 CA014520) for their services. This work was supported in part by the use of the Electron Microscopy facility at the William S. Middleton Memorial Veterans Hospital, Madison WI. We acknowledge the technical assistance of Joan Sempf and Traci Niesen.

Funding

This study was supported by a grant from the University of Wisconsin Carbone Cancer Center (RVL), and by NIH Cancer Center Support Grant P30 CA014520-39 (University of Wisconsin Cancer Center).

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Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA

    • Heather Hardin
    • , Holly Helein
    • , Kristy Meyer
    • , Samantha Robertson
    • , Ranran Zhang
    • , Weixiong Zhong
    •  & Ricardo V. Lloyd

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Ricardo V. Lloyd.

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DOI

https://doi.org/10.1038/s41374-018-0065-0