IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling.
The tumor microenvironment is composed of different types of stromal cells that represent a key component of tumor progression. Cancer-associated fibroblasts (CAFs) secrete several factors that promote tumorigenesis. The purpose of this study was to clarify the role of the interleukin-6 (IL-6) secreted from CAFs in the communication between CAFs and NSCLC cells that modulates chemoresistance.



We used standard NSCLC cell lines as well as NSCLC cells, lung normal fibroblasts, and CAFs obtained from specimens from patients with NSCLC to evaluate phenotypic changes. Immunohistochemical analysis was also utilized to examine the stromal changes in tumor specimens obtained from patients with NSCLC who had undergone chemotherapy.



IL-6 significantly increased transforming growth factor-β1-induced epithelial-to-mesenchymal transition (EMT) changes in cancer cells. Cisplatin treatment increased expression of transforming growth factor-β in cancer cells, and the conditioned media from cancer cells activated fibroblasts and increased their IL-6 production. Expression of IL-6 was increased in CAFs compared with in lung normal fibroblasts. The conditioned media from CAFs induced EMT and resistance to cisplatin in NSCLC cells through IL-6 signaling. Immunohistochemical analysis showed that stromal IL-6 expression was correlated with EMT changes in cancer cells as well as with a diffuse distribution of smooth muscle actin-stained fibroblasts. Univariate and multivariate analyses indicated that stromal IL-6 expression was an independent prognostic factor in patients with NSCLC.



IL-6 from CAFs enhanced EMT in NSCLC cells. IL-6 may contribute to maintenance of a paracrine loop that functions as part of the communication between CAFs and NSCLC cells, resulting in chemoresistance.
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: yshintani@thoracic.med.osaka-u.ac.jp.
Yasushi
Y
Shintani
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Ayako
A
Fujiwara
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Toru
T
Kimura
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Tomohiro
T
Kawamura
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Soichiro
S
Funaki
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Masato
M
Minami
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Meinoshin
M
Okumura
D000072645:Cancer-Associated Fibroblasts / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology
C508600:IL6 protein, human; D015850:Interleukin-6; D016212:Transforming Growth Factor beta
Epithelial-mesenchymal transition; Fibroblast; IL-6; NSCLC; TGF-β