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EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation

A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assa...

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Autores principales: Flores, Miguel A., Fortea, Paula, Trinidad, Eva M., García, Dolores, Soler, Gloria, Ortuño, Francisco J., Zapata, Agustín G., Alonso, Luis M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217033/
https://www.ncbi.nlm.nih.gov/pubmed/27374180
http://dx.doi.org/10.18632/oncotarget.10311
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author Flores, Miguel A.
Fortea, Paula
Trinidad, Eva M.
García, Dolores
Soler, Gloria
Ortuño, Francisco J.
Zapata, Agustín G.
Alonso, Luis M.
author_facet Flores, Miguel A.
Fortea, Paula
Trinidad, Eva M.
García, Dolores
Soler, Gloria
Ortuño, Francisco J.
Zapata, Agustín G.
Alonso, Luis M.
author_sort Flores, Miguel A.
collection PubMed
description A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival.
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spelling pubmed-52170332017-01-17 EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation Flores, Miguel A. Fortea, Paula Trinidad, Eva M. García, Dolores Soler, Gloria Ortuño, Francisco J. Zapata, Agustín G. Alonso, Luis M. Oncotarget Research Paper A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival. Impact Journals LLC 2016-06-27 /pmc/articles/PMC5217033/ /pubmed/27374180 http://dx.doi.org/10.18632/oncotarget.10311 Text en Copyright: © 2016 Flores et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Flores, Miguel A.
Fortea, Paula
Trinidad, Eva M.
García, Dolores
Soler, Gloria
Ortuño, Francisco J.
Zapata, Agustín G.
Alonso, Luis M.
EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
title EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
title_full EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
title_fullStr EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
title_full_unstemmed EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
title_short EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
title_sort ephrina4 plays a critical role in α4 and αl mediated survival of human cll cells during extravasation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217033/
https://www.ncbi.nlm.nih.gov/pubmed/27374180
http://dx.doi.org/10.18632/oncotarget.10311
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