Please use this identifier to cite or link to this item:
Title: Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells
Author: 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.
Keywords: Fibroblasts
Issue Date: 13-Sep-2016
Publisher: Impact Journals
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Oncotarget, 2016, vol. 7, num. 37, p. 59766-59780
Related resource:
ISSN: 1949-2553
Appears in Collections:Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Files in This Item:
File Description SizeFormat 
687441.pdf10.12 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons