Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Osaka, Japan.
Cancer Sci. 2021 Jan;112(1):347-358. doi: 10.1111/cas.14709. Epub 2020 Nov 24.
Interleukin-33 (IL-33), an alarmin released during tissue injury, facilitates the development of cholangiocarcinoma (CCA) in a murine model. However, it is unclear whether IL-33 is associated with human CCA. The aim of this study was to support the following hypothesis: IL-33 is released during hepatectomy for CCA, subsequently facilitating the development of subclinical CCA and eventually leading to recurrent disease. IL-33 expression was assessed in various samples from both humans and mice including resected liver and paired plasma samples collected at hepatectomy and after surgery, and its influences on recurrent disease and patient prognosis were determined. Homogenized human liver samples with high or low IL-33 expression were added to the culture medium of human CCA cells, and the changes in proliferation and migration were evaluated. To examine the effects of inhibiting the IL-33 release induced by hepatectomy, syngraft transplantation of murine CCA cells was performed in C57BL/6J mice with or without IL-33 blockade. The amount of IL-33 released into the plasma during hepatectomy correlated with the background liver expression. High expression of IL-33 in the liver was an independent risk factor for recurrence. Homogenized liver tissue strongly expressing IL-33 increased both the proliferation and migration of tumor cells. Mice who underwent hepatectomy exhibited CCA progression in the remnant liver, whereas blockade of IL-33 during hepatectomy inhibited tumor progression. Thus, we concluded that surgery for CCA with curative intent paradoxically induced IL-33 release, which facilitated CCA recurrence, and anti-IL-33 therapy during hepatectomy might reduce the risk of CCA recurrence.
白细胞介素-33（IL-33）是一种在组织损伤时释放的警报素，它促进了小鼠模型中胆管癌（CCA）的发展。然而，IL-33 是否与人类 CCA 相关尚不清楚。本研究旨在验证以下假说：在 CCA 的肝切除术中释放 IL-33，随后促进亚临床 CCA 的发展，并最终导致复发性疾病。评估了来自人类和小鼠的各种样本中的 IL-33 表达，包括在肝切除术中收集的切除肝脏和配对血浆样本，以及手术后，并确定其对复发性疾病和患者预后的影响。将表达高或低 IL-33 的人肝匀浆添加到人 CCA 细胞的培养基中，评估增殖和迁移的变化。为了研究抑制肝切除术后 IL-33 释放的影响，在 C57BL/6J 小鼠中进行了 CCA 细胞的同种异体移植，并用或不用 IL-33 阻断。肝切除术后释放到血浆中的 IL-33 量与背景肝表达相关。肝中 IL-33 的高表达是复发的独立危险因素。强烈表达 IL-33 的肝匀浆增加了肿瘤细胞的增殖和迁移。接受肝切除术的小鼠在剩余肝脏中表现出 CCA 进展，而在肝切除术中阻断 IL-33 则抑制了肿瘤进展。因此，我们得出结论，具有治愈意图的 CCA 手术会诱发 IL-33 释放，从而促进 CCA 的复发，而肝切除术中的抗-IL-33 治疗可能会降低 CCA 复发的风险。
