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.

Cancer-associated Fibroblast–promoted LncRNA DNM3OS Confers Radioresistance by Regulating DNA Damage Response in Esophageal Squamous Cell Carcinoma

“…In parallel, tumor cells facilitate the transformation of normal fibroblasts into CAFs, which in turn enhance the malignant ability of tumor cells (4,25). Our previous studies revealed that CAFs were involved in tumor chemoradioresponse by secretion of chemokines and cytokines (7,8). We found that the cross-talk between CAFs and tumor cells caused the expressions of CXCL1 and TGFb1 in an autocrine/paracrine signaling loop.…”

“…By use of promoter prediction tool eGPMiner, FOXO1, a transcription factor downstream of the PDGFb/PDGFRb signaling pathway, was predicted to have high affinity with two regions in the DNM3OS promoter. Our previous study had confirmed the expression of FOXO1 was obviously increased at protein level in esophageal cancer cells, which were cultured in CAF CM (7). Herein, we investigated whether FOXO1 was involved in CAF-induced DNM3OS upre-gulation.…”

“…Tumor cells promote the growth and survival of stromal fibroblasts; in parallel, the microenvironment potentiates the activation of signaling pathways that are involved in proliferation, invasion, and survival of tumor cells (4)(5)(6). Our previous study revealed that the cross-talk of esophageal cancer cells and CAFs induced TGFb1 expression in an autocrine/paracrine signaling loop, which resulted in the development of chemoresistance (7). Furthermore, we found CAF-secreted CXCL1 conferred ESCCsignificant radioresistance in vitro and in vivo by regulating DNA damage response (DDR) in a reactive oxygen species-dependent manner (8).…”

Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts

“…Although great efforts have been made to resolve the clinical issue of drug resistance, the underlying mechanism remains largely unclear [69]. Nevertheless, most studies proposed CAFs to be closely associated with chemoresistance acquisition and poor clinical prognosis [70, 71]. Dysregulation of miRNAs in CAFs and exosomal miRNA transfer between cancer cells and the microenvironment is correlated to chemoresistance regulation [72].…”

Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor

“…When it progresses to carcinoma, fibroblasts differentiate into myofibroblasts (CAFs) with expression of growth factors, matrix components, and degrading proteases promoting tumor growth. 6 They protect tumor cells from chemotherapy, [7][8][9] promote tumor invasion by remodeling the ECM structure, 10,11 and affect angiogenesis etc.…”