Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells

The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific convention...

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Autores: Gonçalves-Ribeiro, Samuel, Guillén Díaz-Maroto, Natalia, Berdiel Acer, Mireia, Soriano Izquierdo, Antonio, Guardiola, Jordi, Martínez Villacampa, Mercedes, Salazar Soler, Ramón, Capellá, G. (Gabriel), Villanueva Garatachea, Alberto, Martínez Balibrea, Eva, Molleví, David G.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178653
Acceso en línea:https://hdl.handle.net/2445/178653
Access Level:acceso abierto
Palabra clave:Fibroblasts
Càncer
Farmacologia
Metabolisme
Cancer
Pharmacology
Metabolism
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spelling Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cellsGonçalves-Ribeiro, SamuelGuillén Díaz-Maroto, NataliaBerdiel Acer, MireiaSoriano Izquierdo, AntonioGuardiola, JordiMartínez Villacampa, MercedesSalazar Soler, RamónCapellá, G. (Gabriel)Villanueva Garatachea, AlbertoMartínez Balibrea, EvaMolleví, David G.FibroblastsCàncerFarmacologiaMetabolismeFibroblastsCancerPharmacologyMetabolismThe importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear. Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells. These changes are guided to ensure DNA repair and the correct entrance and exit from mitosis in the presence of chemotherapy. We used conditioned media (CM) from normal-colonic fibroblasts and paired CAFs to assess dose response curves of oxaliplatin and 5-fluorouracil, separately or combined, compared with standard culture medium. We also evaluated a colony-forming assay and cell death to demonstrate the protective role of CAF-CM. Immunofluorescence confirmed the translocation of AKT, P38 and Survivin to the nucleus induced by CAF-soluble factors. We also have shown that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far.Impact Journals2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/178653Articles publicats en revistes (Ciències Clíniques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.18632/oncotarget.11121Oncotarget, 2016, vol. 7, num. 37, p. 59766-59780https://doi.org/10.18632/oncotarget.11121cc-by (c) Gonçalves-Ribeiro, Samuel et al., 2016https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1786532026-05-27T06:46:51Z
dc.title.none.fl_str_mv Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
title Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
spellingShingle Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
Gonçalves-Ribeiro, Samuel
Fibroblasts
Càncer
Farmacologia
Metabolisme
Fibroblasts
Cancer
Pharmacology
Metabolism
title_short Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
title_full Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
title_fullStr Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
title_full_unstemmed Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
title_sort Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
dc.creator.none.fl_str_mv Gonçalves-Ribeiro, Samuel
Guillén Díaz-Maroto, Natalia
Berdiel Acer, Mireia
Soriano Izquierdo, Antonio
Guardiola, Jordi
Martínez Villacampa, Mercedes
Salazar Soler, Ramón
Capellá, G. (Gabriel)
Villanueva Garatachea, Alberto
Martínez Balibrea, Eva
Molleví, David G.
author Gonçalves-Ribeiro, Samuel
author_facet Gonçalves-Ribeiro, Samuel
Guillén Díaz-Maroto, Natalia
Berdiel Acer, Mireia
Soriano Izquierdo, Antonio
Guardiola, Jordi
Martínez Villacampa, Mercedes
Salazar Soler, Ramón
Capellá, G. (Gabriel)
Villanueva Garatachea, Alberto
Martínez Balibrea, Eva
Molleví, David G.
author_role author
author2 Guillén Díaz-Maroto, Natalia
Berdiel Acer, Mireia
Soriano Izquierdo, Antonio
Guardiola, Jordi
Martínez Villacampa, Mercedes
Salazar Soler, Ramón
Capellá, G. (Gabriel)
Villanueva Garatachea, Alberto
Martínez Balibrea, Eva
Molleví, David G.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Fibroblasts
Càncer
Farmacologia
Metabolisme
Fibroblasts
Cancer
Pharmacology
Metabolism
topic Fibroblasts
Càncer
Farmacologia
Metabolisme
Fibroblasts
Cancer
Pharmacology
Metabolism
description The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear. Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells. These changes are guided to ensure DNA repair and the correct entrance and exit from mitosis in the presence of chemotherapy. We used conditioned media (CM) from normal-colonic fibroblasts and paired CAFs to assess dose response curves of oxaliplatin and 5-fluorouracil, separately or combined, compared with standard culture medium. We also evaluated a colony-forming assay and cell death to demonstrate the protective role of CAF-CM. Immunofluorescence confirmed the translocation of AKT, P38 and Survivin to the nucleus induced by CAF-soluble factors. We also have shown that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178653
url https://hdl.handle.net/2445/178653
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.11121
Oncotarget, 2016, vol. 7, num. 37, p. 59766-59780
https://doi.org/10.18632/oncotarget.11121
dc.rights.none.fl_str_mv cc-by (c) Gonçalves-Ribeiro, Samuel et al., 2016
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Gonçalves-Ribeiro, Samuel et al., 2016
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Clíniques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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