Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma.
Adenocarcinoma
/ metabolism
Animals
Antineoplastic Agents
/ pharmacology
Cancer-Associated Fibroblasts
/ metabolism
Cell Line, Tumor
Cell Movement
/ drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
/ genetics
Esophageal Neoplasms
/ metabolism
Humans
Interleukin-6
/ metabolism
Mice
Radiation Tolerance
Stromal Cells
/ metabolism
Tissue Culture Techniques
Xenograft Model Antitumor Assays
IL-6
epithelial-to-mesenchymal transition
esophageal adenocarcinoma
therapy resistance
tumor stroma
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
05 02 2019
05 02 2019
Historique:
pubmed:
24
1
2019
medline:
17
4
2019
entrez:
24
1
2019
Statut:
ppublish
Résumé
Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6-producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
Identifiants
pubmed: 30670657
pii: 1820459116
doi: 10.1073/pnas.1820459116
pmc: PMC6369811
doi:
Substances chimiques
Antineoplastic Agents
0
Interleukin-6
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2237-2242Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Conflict of interest statement: M.F.B. has received research funding from Celgene. H.W.M. v.L. has acted as a consultant for Celgene, Eli Lilly and Company, Nordic Pharma Group, and Philips and has received research grants from Amgen, Bayer Schering Pharma AG, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, Nordic Pharma Group, Philips, and Roche Pharmaceuticals. None were involved in drafting the manuscript.
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