CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance

Abstract Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD...

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Autores principales:	Koran S. Harris, Lihong Shi, Brittni M. Foster, Mary E. Mobley, Phyllis L. Elliott, Conner J. Song, Kounosuke Watabe, Carl D. Langefeld, Bethany A. Kerr
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/31937ecc75f747969043b5ed6e2fc7e4
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spelling	oai:doaj.org-article:31937ecc75f747969043b5ed6e2fc7e42021-12-02T15:22:57ZCD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance10.1038/s41598-021-81126-62045-2322https://doaj.org/article/31937ecc75f747969043b5ed6e2fc7e42021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81126-6https://doaj.org/toc/2045-2322Abstract Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.Koran S. HarrisLihong ShiBrittni M. FosterMary E. MobleyPhyllis L. ElliottConner J. SongKounosuke WatabeCarl D. LangefeldBethany A. KerrNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Koran S. Harris Lihong Shi Brittni M. Foster Mary E. Mobley Phyllis L. Elliott Conner J. Song Kounosuke Watabe Carl D. Langefeld Bethany A. Kerr CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance
description	Abstract Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.
format	article
author	Koran S. Harris Lihong Shi Brittni M. Foster Mary E. Mobley Phyllis L. Elliott Conner J. Song Kounosuke Watabe Carl D. Langefeld Bethany A. Kerr
author_facet	Koran S. Harris Lihong Shi Brittni M. Foster Mary E. Mobley Phyllis L. Elliott Conner J. Song Kounosuke Watabe Carl D. Langefeld Bethany A. Kerr
author_sort	Koran S. Harris
title	CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance
title_short	CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance
title_full	CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance
title_fullStr	CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance
title_full_unstemmed	CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance
title_sort	cd117/c-kit defines a prostate csc-like subpopulation driving progression and tki resistance
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/31937ecc75f747969043b5ed6e2fc7e4
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CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance

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