CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.

The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, the role of these cells in the development, progression and response to therapy in colon cancer rema...

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Autores principales:	Laura M Lopez-Sánchez, Carla Jimenez, Araceli Valverde, Vanessa Hernandez, Jon Peñarando, Antonio Martinez, Chary Lopez-Pedrera, Juan R Muñoz-Castañeda, Juan R De la Haba-Rodríguez, Enrique Aranda, Antonio Rodriguez-Ariza
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/638a2701b50d4fbcb5190a00303e6296
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spelling	oai:doaj.org-article:638a2701b50d4fbcb5190a00303e62962021-11-18T08:15:33ZCoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.1932-620310.1371/journal.pone.0099143https://doaj.org/article/638a2701b50d4fbcb5190a00303e62962014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24932611/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, the role of these cells in the development, progression and response to therapy in colon cancer remains undefined. Therefore, the main objective of this study was to investigate the generation of PGCCs in colon cancer cells and identify mechanisms of formation. Treatment of HCT-116 and Caco-2 colon cancer cells with the hypoxia mimic CoCl2 induced the formation of cells with larger cell and nuclear size (PGCCs), while the cells with normal morphology were selectively eliminated. Cytometric analysis showed that CoCl2 treatment induced G2 cell cycle arrest and the generation of a polyploid cell subpopulation with increased cellular DNA content. Polyploidy of hypoxia-induced PGCCs was confirmed by FISH analysis. Furthermore, CoCl2 treatment effectively induced the stabilization of HIF-1α, the differential expression of a truncated form of p53 (p47) and decreased levels of cyclin D1, indicating molecular mechanisms associated with cell cycle arrest at G2. Generation of PGCCs also contributed to expansion of a cell subpopulation with cancer stem cells (CSCs) characteristics, as indicated by colonosphere formation assays, and enhanced chemoresistance to 5-fluorouracil and oxaliplatin. In conclusion, the pharmacological induction of hypoxia in colon cancer cells causes the formation of PGCCs, the expansion of a cell subpopulation with CSC characteristics and chemoresistance. The molecular mechanisms involved, including the stabilization of HIF-1 α, the involvement of p53/p47 isoform and cell cycle arrest at G2, suggest novel targets to prevent tumor relapse and treatment failure in colon cancer.Laura M Lopez-SánchezCarla JimenezAraceli ValverdeVanessa HernandezJon PeñarandoAntonio MartinezChary Lopez-PedreraJuan R Muñoz-CastañedaJuan R De la Haba-RodríguezEnrique ArandaAntonio Rodriguez-ArizaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e99143 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laura M Lopez-Sánchez Carla Jimenez Araceli Valverde Vanessa Hernandez Jon Peñarando Antonio Martinez Chary Lopez-Pedrera Juan R Muñoz-Castañeda Juan R De la Haba-Rodríguez Enrique Aranda Antonio Rodriguez-Ariza CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
description	The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, the role of these cells in the development, progression and response to therapy in colon cancer remains undefined. Therefore, the main objective of this study was to investigate the generation of PGCCs in colon cancer cells and identify mechanisms of formation. Treatment of HCT-116 and Caco-2 colon cancer cells with the hypoxia mimic CoCl2 induced the formation of cells with larger cell and nuclear size (PGCCs), while the cells with normal morphology were selectively eliminated. Cytometric analysis showed that CoCl2 treatment induced G2 cell cycle arrest and the generation of a polyploid cell subpopulation with increased cellular DNA content. Polyploidy of hypoxia-induced PGCCs was confirmed by FISH analysis. Furthermore, CoCl2 treatment effectively induced the stabilization of HIF-1α, the differential expression of a truncated form of p53 (p47) and decreased levels of cyclin D1, indicating molecular mechanisms associated with cell cycle arrest at G2. Generation of PGCCs also contributed to expansion of a cell subpopulation with cancer stem cells (CSCs) characteristics, as indicated by colonosphere formation assays, and enhanced chemoresistance to 5-fluorouracil and oxaliplatin. In conclusion, the pharmacological induction of hypoxia in colon cancer cells causes the formation of PGCCs, the expansion of a cell subpopulation with CSC characteristics and chemoresistance. The molecular mechanisms involved, including the stabilization of HIF-1 α, the involvement of p53/p47 isoform and cell cycle arrest at G2, suggest novel targets to prevent tumor relapse and treatment failure in colon cancer.
format	article
author	Laura M Lopez-Sánchez Carla Jimenez Araceli Valverde Vanessa Hernandez Jon Peñarando Antonio Martinez Chary Lopez-Pedrera Juan R Muñoz-Castañeda Juan R De la Haba-Rodríguez Enrique Aranda Antonio Rodriguez-Ariza
author_facet	Laura M Lopez-Sánchez Carla Jimenez Araceli Valverde Vanessa Hernandez Jon Peñarando Antonio Martinez Chary Lopez-Pedrera Juan R Muñoz-Castañeda Juan R De la Haba-Rodríguez Enrique Aranda Antonio Rodriguez-Ariza
author_sort	Laura M Lopez-Sánchez
title	CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
title_short	CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
title_full	CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
title_fullStr	CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
title_full_unstemmed	CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
title_sort	cocl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/638a2701b50d4fbcb5190a00303e6296
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CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer.

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