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Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas

Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stem-like cell (CSC) properties. Platelet-derived growth factor receptors α and β (PDGFR-α/β) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of P...

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Autores principales: Chang, Kevin K., Yoon, Changhwan, Yi, Brendan C., Tap, William D., Simon, M. Celeste, Yoon, Sam S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006341/
https://www.ncbi.nlm.nih.gov/pubmed/29915281
http://dx.doi.org/10.1038/s41389-018-0059-1
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author Chang, Kevin K.
Yoon, Changhwan
Yi, Brendan C.
Tap, William D.
Simon, M. Celeste
Yoon, Sam S.
author_facet Chang, Kevin K.
Yoon, Changhwan
Yi, Brendan C.
Tap, William D.
Simon, M. Celeste
Yoon, Sam S.
author_sort Chang, Kevin K.
collection PubMed
description Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stem-like cell (CSC) properties. Platelet-derived growth factor receptors α and β (PDGFR-α/β) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-α/β in sarcoma CSCs. PDGFR-α/β activity and the effects of PDGFR-α/β inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-α/β activity was significantly higher in cells grown as spheroids (to enrich for CSCs) and in cells sorted for CD133 expression (a marker of sarcoma CSCs). Self-renewal transcription factors Nanog, Oct4, and Slug and epithelial-to-mesenchymal transition (EMT) proteins Snail, Slug, and Zeb1 were also significantly higher in spheroids cells and CD133((+)) cells. Spheroid cells and CD133((+)) cells demonstrated 2.9- to 4.2-fold greater migration and invasion and resistance to doxorubicin chemotherapy. Inhibition of PDGFR-α/β in CSCs using shRNA or pharmacologic inhibitors reduced expression of certain self-renewal and EMT proteins, reduced spheroid formation by 74–82%, reduced migration and invasion by 73–80%, and reversed chemotherapy resistance. In mouse xenograft models, combining PDGFR-α/β inhibition (using shRNA or imatinib) with doxorubicin had a more-than-additive effect in blocking tumor growth, with enhanced apoptosis, especially in CD133((+)) cells. These results indicate that PDGFR-α/β activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-α/β pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity.
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spelling pubmed-60063412018-06-20 Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas Chang, Kevin K. Yoon, Changhwan Yi, Brendan C. Tap, William D. Simon, M. Celeste Yoon, Sam S. Oncogenesis Article Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stem-like cell (CSC) properties. Platelet-derived growth factor receptors α and β (PDGFR-α/β) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-α/β in sarcoma CSCs. PDGFR-α/β activity and the effects of PDGFR-α/β inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-α/β activity was significantly higher in cells grown as spheroids (to enrich for CSCs) and in cells sorted for CD133 expression (a marker of sarcoma CSCs). Self-renewal transcription factors Nanog, Oct4, and Slug and epithelial-to-mesenchymal transition (EMT) proteins Snail, Slug, and Zeb1 were also significantly higher in spheroids cells and CD133((+)) cells. Spheroid cells and CD133((+)) cells demonstrated 2.9- to 4.2-fold greater migration and invasion and resistance to doxorubicin chemotherapy. Inhibition of PDGFR-α/β in CSCs using shRNA or pharmacologic inhibitors reduced expression of certain self-renewal and EMT proteins, reduced spheroid formation by 74–82%, reduced migration and invasion by 73–80%, and reversed chemotherapy resistance. In mouse xenograft models, combining PDGFR-α/β inhibition (using shRNA or imatinib) with doxorubicin had a more-than-additive effect in blocking tumor growth, with enhanced apoptosis, especially in CD133((+)) cells. These results indicate that PDGFR-α/β activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-α/β pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity. Nature Publishing Group UK 2018-06-19 /pmc/articles/PMC6006341/ /pubmed/29915281 http://dx.doi.org/10.1038/s41389-018-0059-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chang, Kevin K.
Yoon, Changhwan
Yi, Brendan C.
Tap, William D.
Simon, M. Celeste
Yoon, Sam S.
Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
title Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
title_full Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
title_fullStr Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
title_full_unstemmed Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
title_short Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
title_sort platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006341/
https://www.ncbi.nlm.nih.gov/pubmed/29915281
http://dx.doi.org/10.1038/s41389-018-0059-1
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