Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou 310002, China.
Department of Pathology, Hangzhou Cancer Hospital, Hangzhou 310002, China.
Cell Death Dis. 2017 May 18;8(5):e2790. doi: 10.1038/cddis.2017.180.
Five-year survival rate of esophageal squamous cell carcinoma (ESCC) patients treated with radiotherapy is <20%. Our study aimed to investigate whether cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, were involved in tumor radioresistance in ESCC. By use of human chemokine/cytokine array, human chemokine CXCL1 was found to be highly expressed in CAFs compared with that in matched normal fibroblasts. Inhibition of CXCL1 expression in CAFs significantly reversed CAF-conferred radioresistance in vitro and in vivo. CAF-secreted CXCL1 inhibited the expression of reactive oxygen species (ROS)-scavenging enzyme superoxide dismutase 1, leading to increased ROS accumulation following radiation, by which DNA damage repair was enhanced and the radioresistance was mediated. CAF-secreted CXCL1 mediated the radioresistance also by activation of Mek/Erk pathway. The cross talk of CAFs and ESCC cells induced CXCL1 expression in an autocrine/paracrine signaling loop, which further enhanced tumor radioresistance. Together, our study highlighted CAF-secreted CXCL1 as an attractive target to reverse tumor radioresistance and can be used as an independent prognostic factor of ESCC patients treated with chemoradiotherapy.
接受放疗的食管鳞状细胞癌（ESCC）患者的五年生存率<20%。我们的研究旨在探讨肿瘤微环境的主要成分之一——癌症相关成纤维细胞（CAF）是否参与 ESCC 的肿瘤放射抵抗。通过使用人趋化因子/细胞因子阵列，发现与匹配的正常成纤维细胞相比，CAF 中高度表达人趋化因子 CXCL1。抑制 CAF 中 CXCL1 的表达可显著逆转 CAF 在体外和体内赋予的放射抵抗。CAF 分泌的 CXCL1 抑制活性氧（ROS）清除酶超氧化物歧化酶 1 的表达，导致放射后 ROS 积累增加，从而增强 DNA 损伤修复，介导放射抵抗。CAF 分泌的 CXCL1 还通过 Mek/Erk 通路的激活介导放射抵抗。CAFs 和 ESCC 细胞的串扰通过自分泌/旁分泌信号环路诱导 CXCL1 表达，进一步增强了肿瘤的放射抵抗性。总之，我们的研究强调了 CAF 分泌的 CXCL1 作为逆转肿瘤放射抵抗的有吸引力的靶点，并可用作接受放化疗的 ESCC 患者的独立预后因素。
