Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

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....

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Vydané v:	Proceedings of the National Academy of Sciences - PNAS Ročník 116; číslo 6; s. 2237
Hlavní autori:	Ebbing, Eva A, van der Zalm, Amber P, Steins, Anne, Creemers, Aafke, Hermsen, Simone, Rentenaar, Rosa, Klein, Michelle, Waasdorp, Cynthia, Hooijer, Gerrit K J, Meijer, Sybren L, Krishnadath, Kausilia K, Punt, Cornelis J A, van Berge Henegouwen, Mark I, Gisbertz, Suzanne S, van Delden, Otto M, Hulshof, Maarten C C M, Medema, Jan Paul, van Laarhoven, Hanneke W M, Bijlsma, Maarten F
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 05.02.2019
Predmet:	Adenocarcinoma - metabolism Adenocarcinoma - pathology Adenocarcinoma - therapy Animals Antineoplastic Agents - pharmacology Cancer-Associated Fibroblasts - metabolism Cell Line, Tumor Cell Movement - drug effects Cell Movement - radiation effects Disease Models, Animal Dose-Response Relationship, Drug Dose-Response Relationship, Radiation Drug Resistance, Neoplasm Epithelial-Mesenchymal Transition - genetics Esophageal Neoplasms - metabolism Esophageal Neoplasms - pathology Esophageal Neoplasms - therapy Humans Interleukin-6 - metabolism Mice Radiation Tolerance Stromal Cells - metabolism Tissue Culture Techniques Xenograft Model Antitumor Assays tumor stroma esophageal adenocarcinoma IL-6 epithelial-to-mesenchymal transition therapy resistance
ISSN:	1091-6490, 1091-6490
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Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1820459116