title: Cancer-associated fibroblasts mediated chemoresistance by a FOXO1/TGFβ1 signaling loop in esophageal squamous cell carcinoma.
abstract: Previous studies on the mechanisms underlying ESCC (esophageal squamous cell carcinoma) chemoresistance only focused on tumor cells while tumor microenvironment has been completely ignored. Our study aimed to clarify the effect of CAFs (cancer-associated fibroblasts), one major component of tumor microenvironment, on the chemoresistance of ESCC. By primary culture, two pairs of CAFs and matched NFs (normal fibroblasts) were isolated from tumor tissues of ESCC patients and matched normal esophageal epithelial tissues, respectively. The association of CAFs and chemoresistance was assessed in esophageal carcinoma cells, in xenograft tumor models and in clinical specimens of ESCC patients. We found CAFs conferred ESCC cells significant resistance to several common chemotherapeutic drugs including cisplatin, taxol, irinotecan (CPT-11), 5-fluorouracil (5-Fu), carboplatin, docetaxel, pharmorubicin, and vincristine. Mechanism studies revealed that blockage of CAFs-secreted TGFβ1 signaling by its receptor TGFβR1 inhibitor LY2157299 significantly reversed the chemoresistance in vitro and in vivo. Furthermore, the crosstalk of CAFs and ESCC cells enhanced the expression and activation of FOXO1, a member of the forkhead transcription factors in the O-box sub-family, inducing TGFβ1 expression in an autocrine/paracrine signaling loop. In 130 ESCC patients, the expression of TGFβ1 in CAFs was significantly associated with overall survival of patients treated with chemoradiotherapy. Together, our study highlighted TGFβ1 expressed in CAFs as an attractive target to reverse tumor chemoresistance, and can be used as an independent prognostic factor of ESCC patients treated with chemoradiotherapy. © 2016 Wiley Periodicals, Inc.
authors: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Hongfang
authors: H
authors: Zhang
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China.|Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan University, Wuhan, Hubei, China.|Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei, China.
authors: Conghua
authors: C
authors: Xie
authors: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Jing
authors: J
authors: Yue
authors: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Zhenzhen
authors: Z
authors: Jiang
authors: Department of Pathology, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Rongjing
authors: R
authors: Zhou
authors: Department of Bio-Informatics, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Ruifei
authors: R
authors: Xie
authors: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Yan
authors: Y
authors: Wang
authors: Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China.
authors: Shixiu
authors: S
authors: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D011720:Pyrazoles; D011804:Quinolines; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C557799:LY-2157299
keywords: ESCC; TGFβ1; autocrine/paracrine signaling loop; cancer-associated fibroblasts; chemoresistance