Table1_Interleukin-6-derived cancer-associated fibroblasts activate STAT3 pathway contributing to gemcitabine resistance in cholangiocarcinoma.pdf

Cancer-associated fibroblasts (CAFs) are the dominant component of the tumor microenvironment (TME) that can be beneficial to the generation and progression of cancer cells leading to chemotherapeutic failure via several mechanisms. Nevertheless, the roles of CAFs on anti-cancer drug response need more empirical evidence in cholangiocarcinoma (CCA). Herein, we examined the oncogenic roles of CAFs on gemcitabine resistance in CCA cells mediated via IL-6/STAT3 activation. Our findings showed that CCA-derived CAFs promote cell viability and enhance gemcitabine resistance in CCA cells through the activation of IL-6/STAT3 signaling. High expression of IL-6R was correlated with a poor overall survival rate and gemcitabine resistance in CCA, indicating that IL-6R can be a prognostic or predictive biomarker for the chemotherapeutic response of CCA patients. Blockade of IL-6R on CCA cells by tocilizumab, an IL-6R humanized antihuman monoclonal antibody, contributed to inhibition of the CAF-CCA interaction leading to enhancement of gemcitabine sensitivity in CCA cells. The results of this study should be helpful for modifying therapeutic regimens aimed at targeting CAF interacting with cancer cells resulting in the suppression of the tumor progression but enhancement of drug sensitivity.

癌相关成纤维细胞（CAFs）是肿瘤微环境（TME）中的主要组成部分，它们可以通过多种机制促进癌细胞的生成和进展，从而导致化疗失败。尽管如此，在胆管癌（CCA）中，癌相关成纤维细胞对抗癌药物反应的作用仍需更多实证研究。本研究中，我们探讨了通过IL-6/STAT3激活介导的癌相关成纤维细胞在CCA细胞对吉西他滨耐药性中的致癌作用。研究发现，源自CCA的癌相关成纤维细胞通过激活IL-6/STAT3信号通路，促进CCA细胞存活并增强其对吉西他滨的耐药性。IL-6R的高表达与CCA患者总生存率低下和吉西他滨耐药性相关，表明IL-6R可能成为化疗反应的预后或预测生物标志物。通过托珠单抗，一种人源化抗人单克隆抗体，阻断CCA细胞上的IL-6R，有助于抑制癌相关成纤维细胞与CCA细胞之间的相互作用，从而增强CCA细胞对吉西他滨的敏感性。本研究结果有助于调整针对与癌细胞相互作用的癌相关成纤维细胞的治疗方案，以期抑制肿瘤进展并增强药物敏感性。