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Linking genomic reorganization to tumor initiation via the giant cell cycle

To investigate the mechanisms underlying our recent paradoxical finding that mitotically incapacitated and genomically unstable polyploid giant cancer cells (PGCCs) are capable of tumor initiation, we labeled ovarian cancer cells with α-tubulin fused to green fluorescent protein, histone-2B fused to...

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Autores principales: Niu, N, Zhang, J, Zhang, N, Mercado-Uribe, I, Tao, F, Han, Z, Pathak, S, Multani, A S, Kuang, J, Yao, J, Bast, R C, Sood, A K, Hung, M-C, Liu, J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177773/
https://www.ncbi.nlm.nih.gov/pubmed/27991913
http://dx.doi.org/10.1038/oncsis.2016.75
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author Niu, N
Zhang, J
Zhang, N
Mercado-Uribe, I
Tao, F
Han, Z
Pathak, S
Multani, A S
Kuang, J
Yao, J
Bast, R C
Sood, A K
Hung, M-C
Liu, J
author_facet Niu, N
Zhang, J
Zhang, N
Mercado-Uribe, I
Tao, F
Han, Z
Pathak, S
Multani, A S
Kuang, J
Yao, J
Bast, R C
Sood, A K
Hung, M-C
Liu, J
author_sort Niu, N
collection PubMed
description To investigate the mechanisms underlying our recent paradoxical finding that mitotically incapacitated and genomically unstable polyploid giant cancer cells (PGCCs) are capable of tumor initiation, we labeled ovarian cancer cells with α-tubulin fused to green fluorescent protein, histone-2B fused to red fluorescent protein and FUCCI (fluorescent ubiquitination cell cycle indicator), and tracked the spatial and time-dependent change in spindle and chromosomal dynamics of PGCCs using live-cell fluorescence time-lapse recording. We found that single-dose (500 nm) treatment with paclitaxel paradoxically initiated endoreplication to form PGCCs after massive cell death. The resulting PGCCs continued self-renewal via endoreplication and further divided by nuclear budding or fragmentation; the small daughter nuclei then acquired cytoplasm, split off from the giant mother cells and acquired competency in mitosis. FUCCI showed that PGCCs divided via truncated endoreplication cell cycle (endocycle or endomitosis). Confocal microscopy showed that PGCCs had pronounced nuclear fragmentation and lacked expression of key mitotic proteins. PGCC-derived daughter cells were capable of long-term proliferation and acquired numerous new genome/chromosome alterations demonstrated by spectral karyotyping. These data prompt us to conceptualize a giant cell cycle composed of four distinct but overlapping phases, initiation, self-renewal, termination and stability. The giant cell cycle may represent a fundamental cellular mechanism to initiate genomic reorganization to generate new tumor-initiating cells in response to chemotherapy-induced stress and contributes to disease relapse.
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spelling pubmed-51777732016-12-23 Linking genomic reorganization to tumor initiation via the giant cell cycle Niu, N Zhang, J Zhang, N Mercado-Uribe, I Tao, F Han, Z Pathak, S Multani, A S Kuang, J Yao, J Bast, R C Sood, A K Hung, M-C Liu, J Oncogenesis Original Article To investigate the mechanisms underlying our recent paradoxical finding that mitotically incapacitated and genomically unstable polyploid giant cancer cells (PGCCs) are capable of tumor initiation, we labeled ovarian cancer cells with α-tubulin fused to green fluorescent protein, histone-2B fused to red fluorescent protein and FUCCI (fluorescent ubiquitination cell cycle indicator), and tracked the spatial and time-dependent change in spindle and chromosomal dynamics of PGCCs using live-cell fluorescence time-lapse recording. We found that single-dose (500 nm) treatment with paclitaxel paradoxically initiated endoreplication to form PGCCs after massive cell death. The resulting PGCCs continued self-renewal via endoreplication and further divided by nuclear budding or fragmentation; the small daughter nuclei then acquired cytoplasm, split off from the giant mother cells and acquired competency in mitosis. FUCCI showed that PGCCs divided via truncated endoreplication cell cycle (endocycle or endomitosis). Confocal microscopy showed that PGCCs had pronounced nuclear fragmentation and lacked expression of key mitotic proteins. PGCC-derived daughter cells were capable of long-term proliferation and acquired numerous new genome/chromosome alterations demonstrated by spectral karyotyping. These data prompt us to conceptualize a giant cell cycle composed of four distinct but overlapping phases, initiation, self-renewal, termination and stability. The giant cell cycle may represent a fundamental cellular mechanism to initiate genomic reorganization to generate new tumor-initiating cells in response to chemotherapy-induced stress and contributes to disease relapse. Nature Publishing Group 2016-12 2016-12-19 /pmc/articles/PMC5177773/ /pubmed/27991913 http://dx.doi.org/10.1038/oncsis.2016.75 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Niu, N
Zhang, J
Zhang, N
Mercado-Uribe, I
Tao, F
Han, Z
Pathak, S
Multani, A S
Kuang, J
Yao, J
Bast, R C
Sood, A K
Hung, M-C
Liu, J
Linking genomic reorganization to tumor initiation via the giant cell cycle
title Linking genomic reorganization to tumor initiation via the giant cell cycle
title_full Linking genomic reorganization to tumor initiation via the giant cell cycle
title_fullStr Linking genomic reorganization to tumor initiation via the giant cell cycle
title_full_unstemmed Linking genomic reorganization to tumor initiation via the giant cell cycle
title_short Linking genomic reorganization to tumor initiation via the giant cell cycle
title_sort linking genomic reorganization to tumor initiation via the giant cell cycle
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177773/
https://www.ncbi.nlm.nih.gov/pubmed/27991913
http://dx.doi.org/10.1038/oncsis.2016.75
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