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Open AccessArticle

Zebrafish Microenvironment Elevates EMT and CSC-Like Phenotype of Engrafted Prostate Cancer Cells

Institute of Biology, Leiden University, 2311 EZ Leiden, Netherlands
Department of Molecular Biology, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland
Center for Biomedical Research, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
Department for BioMedical Research, Bern University, 3012 Bern, Switzerland
Department of Urology, Inselspital, 3008 Bern, Switzerland
Author to whom correspondence should be addressed.
Cells 2020, 9(4), 797;
Received: 29 February 2020 / Revised: 22 March 2020 / Accepted: 23 March 2020 / Published: 26 March 2020
To visually and genetically trace single-cell dynamics of human prostate cancer (PCa) cells at the early stage of metastasis, a zebrafish (ZF) xenograft model was employed. The phenotypes of intravenously transplanted fluorescent cells were monitored by high-resolution, single-cell intravital confocal and light-sheet imaging. Engrafted osteotropic, androgen independent PCa cells were extravasated from caudle vein, invaded the neighboring tissue, proliferated and formed experimental metastases around caudal hematopoietic tissue (CHT) in four days. Gene expression comparison between cells in culture and in CHT revealed that engrafted PCa cells responded to the ZF microenvironment by elevating expression of epithelial–mesenchymal transition (EMT) and stemness markers. Next, metastatic potentials of ALDHhi cancer stem-like cells (CSCs) and ALDHlow non-CSCs were analyzed in ZF. Engraftment of CSCs induced faster metastatic onset, however after six days both cell subpopulations equally responded to the ZF microenvironment, resulting in the same increase of stemness genes expression including Nanog, Oct-4 and Cripto. Knockdown of Cripto significantly reduced the vimentin/E-cadherin ratio in engrafted cells, indicating that Cripto is required for transduction of the microenvironment signals from the ZF niche to increase mesenchymal potential of cells. Targeting of either Cripto or EMT transcriptional factors Snail 1 and Zeb1 significantly suppressed metastatic growth. These data indicated that zebrafish microenvironment governed the CSC/EMT plasticity of human PCa cells promoting metastasis initiation. View Full-Text
Keywords: Zebrafish xenograft model; prostate cancer; cell plasticity Zebrafish xenograft model; prostate cancer; cell plasticity
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Chen, L.; Boleslaw Olszewski, M.; Kruithof-de Julio, M.; Snaar-Jagalska, B.E. Zebrafish Microenvironment Elevates EMT and CSC-Like Phenotype of Engrafted Prostate Cancer Cells. Cells 2020, 9, 797.

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