Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.

<h4>Background</h4>Cancer stem cells/initiating cells (CSC/CIC), are thought to exist as a small population in malignant tissues. They are resistant to conventional cancer treatments and possibly underlie post-treatment relapse. The CIC population can be targeted with capsid modified onc...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Laura Ahtiainen, Cristina Mirantes, Tiina Jahkola, Sophie Escutenaire, Iulia Diaconu, Pamela Osterlund, Anna Kanerva, Vincenzo Cerullo, Akseli Hemminki
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e980cd7d5ead401aa6fc1c566dc14e69
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e980cd7d5ead401aa6fc1c566dc14e69
record_format	dspace
spelling	oai:doaj.org-article:e980cd7d5ead401aa6fc1c566dc14e692021-11-18T07:02:26ZDefects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.1932-620310.1371/journal.pone.0013859https://doaj.org/article/e980cd7d5ead401aa6fc1c566dc14e692010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21079774/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Cancer stem cells/initiating cells (CSC/CIC), are thought to exist as a small population in malignant tissues. They are resistant to conventional cancer treatments and possibly underlie post-treatment relapse. The CIC population can be targeted with capsid modified oncolytic adenoviruses.<h4>Methodology/principal findings</h4>We studied the mechanisms of innate immunity to oncolytic adenovirus Ad5/3-Delta24 in conventional treatment resistant non-CIC breast cancer cells, breast cancer CD44(+)/CD24(-/low) CIC population and normal breast tissue CD44(+)/CD24(-/low) stem cells. We compared virus recognition by pattern recognition receptors for adenovirus, Toll-like receptors (TLR) 2 and 9 and virus induced type I interferon (IFN) response regulation in these cell types. We show TLR mediated virus recognition in these non-immune cell types. Normal tissue stem cells have intact type I IFN signaling. Furthermore, TLR9 and TLR2 reside constantly in recognition sites, implying constant activation. In contrast, breast cancer CD44(+)/CD24(-/low) CIC have dysregulated innate immune responses featuring dysfunctional virus recognition caused by impaired trafficking of TLR9 and cofactor MyD88 and the absence of TLR2, having a deleterious impact on TLR pattern recognition receptor signaling. Furthermore, the CIC have increased inhibitory signaling via the suppressor of cytokine signaling/Tyro3/Axl/Mer receptor tyrosine kinase (SOCS/TAM) pathway. These defects in contribute to dysfunctional induction of type I IFN response in CIC and therefore permissivity to oncolytic adenovirus.<h4>Conclusions/significance</h4>CICs may underlie the incurable nature of relapsed or metastatic cancers and are therefore an important target regarding diagnostic and prognostic aspects as well as treatment of the disease. This study addresses the mechanisms of innate infection immunity in stem cells deepening the understanding of stem cell biology and may benefit not only virotherapy but also immunotherapy in general.Laura AhtiainenCristina MirantesTiina JahkolaSophie EscutenaireIulia DiaconuPamela OsterlundAnna KanervaVincenzo CerulloAkseli HemminkiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 11, p e13859 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laura Ahtiainen Cristina Mirantes Tiina Jahkola Sophie Escutenaire Iulia Diaconu Pamela Osterlund Anna Kanerva Vincenzo Cerullo Akseli Hemminki Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
description	<h4>Background</h4>Cancer stem cells/initiating cells (CSC/CIC), are thought to exist as a small population in malignant tissues. They are resistant to conventional cancer treatments and possibly underlie post-treatment relapse. The CIC population can be targeted with capsid modified oncolytic adenoviruses.<h4>Methodology/principal findings</h4>We studied the mechanisms of innate immunity to oncolytic adenovirus Ad5/3-Delta24 in conventional treatment resistant non-CIC breast cancer cells, breast cancer CD44(+)/CD24(-/low) CIC population and normal breast tissue CD44(+)/CD24(-/low) stem cells. We compared virus recognition by pattern recognition receptors for adenovirus, Toll-like receptors (TLR) 2 and 9 and virus induced type I interferon (IFN) response regulation in these cell types. We show TLR mediated virus recognition in these non-immune cell types. Normal tissue stem cells have intact type I IFN signaling. Furthermore, TLR9 and TLR2 reside constantly in recognition sites, implying constant activation. In contrast, breast cancer CD44(+)/CD24(-/low) CIC have dysregulated innate immune responses featuring dysfunctional virus recognition caused by impaired trafficking of TLR9 and cofactor MyD88 and the absence of TLR2, having a deleterious impact on TLR pattern recognition receptor signaling. Furthermore, the CIC have increased inhibitory signaling via the suppressor of cytokine signaling/Tyro3/Axl/Mer receptor tyrosine kinase (SOCS/TAM) pathway. These defects in contribute to dysfunctional induction of type I IFN response in CIC and therefore permissivity to oncolytic adenovirus.<h4>Conclusions/significance</h4>CICs may underlie the incurable nature of relapsed or metastatic cancers and are therefore an important target regarding diagnostic and prognostic aspects as well as treatment of the disease. This study addresses the mechanisms of innate infection immunity in stem cells deepening the understanding of stem cell biology and may benefit not only virotherapy but also immunotherapy in general.
format	article
author	Laura Ahtiainen Cristina Mirantes Tiina Jahkola Sophie Escutenaire Iulia Diaconu Pamela Osterlund Anna Kanerva Vincenzo Cerullo Akseli Hemminki
author_facet	Laura Ahtiainen Cristina Mirantes Tiina Jahkola Sophie Escutenaire Iulia Diaconu Pamela Osterlund Anna Kanerva Vincenzo Cerullo Akseli Hemminki
author_sort	Laura Ahtiainen
title	Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
title_short	Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
title_full	Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
title_fullStr	Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
title_full_unstemmed	Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
title_sort	defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/e980cd7d5ead401aa6fc1c566dc14e69
work_keys_str_mv	AT lauraahtiainen defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT cristinamirantes defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT tiinajahkola defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT sophieescutenaire defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT iuliadiaconu defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT pamelaosterlund defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT annakanerva defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT vincenzocerullo defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus AT akselihemminki defectsininnateimmunityrenderbreastcancerinitiatingcellspermissivetooncolyticadenovirus
_version_	1718424075879055360

Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.

Ejemplares similares