title: Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells.
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.
authors: Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Samuel
authors: S
authors: Gonçalves-Ribeiro
authors: Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Natalia Guillen
authors: NG
authors: Díaz-Maroto
authors: Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Mireia
authors: M
authors: Berdiel-Acer
authors: Gastroenterology Department, Endoscopy Unit, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Antonio
authors: A
authors: Soriano
authors: Gastroenterology Department, Endoscopy Unit, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Jordi
authors: J
authors: Guardiola
authors: Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Mercedes
authors: M
authors: Martínez-Villacampa
authors: Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Ramon
authors: R
authors: Salazar
authors: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Gabriel
authors: G
authors: Capellà
authors: Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: Alberto
authors: A
authors: Villanueva
authors: Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IGTP, Badalona, Catalonia, Spain.
authors: Eva
authors: E
authors: Martínez-Balibrea
authors: Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Catalonia, Spain.
authors: David G
authors: DG
authors: Molleví
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D017077:Culture Media, Conditioned; D051034:Inhibitor of Apoptosis Proteins; D009944:Organoplatinum Compounds; D050796:STAT3 Transcription Factor; D000077022:Survivin; D000077150:Oxaliplatin; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil
keywords: carcinoma-associated fibroblasts; chemotherapy; colorectal cancer; microenvironment-mediated drug resistance; resistance