Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland; Cancer Immunology and Immunotherapy Group, Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland; Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland.
Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway.
Cancer Lett. 2024 Nov 1;604:217253. doi: 10.1016/j.canlet.2024.217253. Epub 2024 Sep 14.
Resistance to neoadjuvant chemoradiation therapy (neo-CRT) is a significant clinical problem in the treatment of locally advanced rectal cancer. Identification of novel therapeutic targets and biomarkers predicting therapeutic response is required to improve patient outcomes. Increasing evidence supports a role for the complement system in resistance to anti-cancer therapy. In this study, increased expression of complement effectors C3 and C5 and increased production of anaphylatoxins, C3a and C5a, was observed in radioresistant rectal cancer cells. Modulation of the central complement effector, C3, was demonstrated to functionally alter the radioresponse, with C3 overexpression significantly enhancing radioresistance, whilst C3 inhibition significantly increased sensitivity to a clinically-relevant dose of radiation. Inhibition of C3 was demonstrated to increase DNA damage and alter cell cycle distribution, mediating a shift towards a radiosensitive cell cycle phenotype suggesting a role for C3 in reprogramming of the tumoural radioresponse. Expression of the complement effectors C3 and C5 was significantly increased in human rectal tumour tissue, as was expression of CFB, a component of the alternative pathway of activation. Elevated levels of C3a and C5b-9 in pre-treatment sera from rectal cancer patients was associated with subsequent poor responses to neo-CRT and poorer survival. Together these data demonstrate a role for complement in the radioresistance of rectal cancer and identify key complement components as potential biomarkers predicting response to neo-CRT and outcome in rectal cancer.
新辅助放化疗（neo-CRT）耐药是局部晚期直肠癌治疗中的一个重大临床问题。需要确定新的治疗靶点和预测治疗反应的生物标志物，以改善患者的预后。越来越多的证据支持补体系统在抗癌治疗耐药中的作用。在这项研究中，在耐辐射的直肠癌细胞中观察到补体效应物 C3 和 C5 的表达增加，以及过敏毒素 C3a 和 C5a 的产生增加。调节中央补体效应物 C3 被证明可在功能上改变放射反应，C3 过表达显著增强放射抗性，而 C3 抑制显著增加对临床相关剂量辐射的敏感性。抑制 C3 被证明可增加 DNA 损伤并改变细胞周期分布，介导向放射敏感的细胞周期表型的转变，提示 C3 在肿瘤放射反应的重编程中发挥作用。在人类直肠肿瘤组织中，补体效应物 C3 和 C5 的表达显著增加，补体激活替代途径的组成部分 CFB 的表达也增加。直肠癌患者治疗前血清中 C3a 和 C5b-9 的水平升高与随后对 neo-CRT 的反应不良和生存不良相关。这些数据共同表明补体在直肠癌的放射抗性中起作用，并确定关键的补体成分作为预测 neo-CRT 反应和直肠癌预后的潜在生物标志物。
