Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea.
Hubrecht Institute, Cancer Genomics Netherlands, UMC Utrecht, 3584CT, Utrecht, Netherlands.
Nat Commun. 2020 Oct 21;11(1):5321. doi: 10.1038/s41467-020-19173-2.
5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in Apc/Lgr5 mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.
5-氟尿嘧啶（5-FU）仍然是结直肠癌（CRC）的一线治疗药物。尽管 5-FU 最初使肿瘤体积缩小，但化疗后的复发是 CRC 患者获得有效临床效果的障碍。在这里，我们证明 p53 促进 WNT3 的转录，导致 APC/Lgr5 小鼠、CRC 患者来源的肿瘤类器官（PDTOs）和患者来源的肿瘤细胞（PDCs）中 WNT/β-catenin 通路的激活。通过这种调节，5-FU 在残留肿瘤中诱导癌症干细胞（CSCs）的激活和富集，导致治疗后复发。WNT 抑制剂和 5-FU 的联合治疗可有效抑制 CSCs，并减少治疗停止后的肿瘤再生长。这些发现表明 p53 是 5-FU 诱导的 CSC 通过 WNT/β-catenin 信号通路激活的关键介质，并强调了联合应用 WNT 抑制剂和 5-FU 的治疗策略的重要性，这是改善当前基于 5-FU 的 CRC 患者治疗效果不佳的一种有吸引力的治疗策略。
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