荷兰癌症研究所Jacco van Rheenen等研究人员合作发现，发情周期阶段影响乳腺肿瘤对化疗的敏感性。相关论文于2024年12月4日在线发表在《自然》杂志上。

据研究人员介绍，即使肿瘤属于相同的分子或组织学亚型，乳腺癌对新辅助化疗（NAC）的反应差异显著。

研究人员确定了发情周期作为这种异质性的重要因素。在三种乳腺癌小鼠模型中，研究人员发现当治疗在间情期开始时，相较于在发情期开始时，NAC的反应较弱。在回顾性绝经前人类患者队列中也观察到了类似的结果。

从机制上讲，间情期表现出系统性和局部的变化，包括：（1）与化疗抗性相关的上皮-间充质转化的细胞数量增加；（2）肿瘤血管直径减小，提示可能对药物敏感性和输送的限制。

此外，间情期特征为巨噬细胞的增多，先前已与化疗抗性诱导相关。尽管NAC会干扰发情周期，但这种增多的巨噬细胞数量仍然存在，且巨噬细胞的去除可缓解在间情期开始治疗时观察到的疗效降低。

这些数据共同表明，发情周期是决定化疗敏感性的关键日内节律，值得未来临床研究利用最佳治疗启动时机以提高化疗效果。

附：英文原文

Title: The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy

Author: Bornes, Laura, van Winden, Lennart J., Geurts, Veerle C. M., de Bruijn, Beaunelle, Azarang, Leyla, Lanfermeijer, Mirthe, Caruso, Marika, Proost, Natalie, Boeije, Manon, Lohuis, Jeroen O., Belthier, Guillaume, Noguera Delgado, Eullia, de Gruil, Nadia, Kroep, Judith R., van de Ven, Marieke, Menezes, Renee, Wesseling, Jelle, Kok, Marleen, Linn, Sabine, Broeks, Annegien, van Rossum, Huub H., Scheele, Colinda L. G. J., van Rheenen, Jacco

Issue&Volume: 2024-12-04

Abstract: The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype1. Here we identify the oestrous cycle as an important contributor to this heterogeneity. In three mouse models of breast cancer, we show reduced responses to NAC when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage. Similar findings were observed in retrospective premenopausal cohorts of human patients. Mechanistically, the dioestrus stage exhibits systemic and localized changes, including (1) an increased number of cells undergoing epithelial-to-mesenchymal transition linked to chemoresistance2,3,4 and (2) decreased tumour vessel diameter, suggesting potential constraints to drug sensitivity and delivery. In addition, an elevated presence of macrophages, previously associated with chemoresistance induction5, characterizes the dioestrus phase. Whereas NAC disrupts the oestrous cycle, this elevated macrophage prevalence persists and depletion of macrophages mitigates the reduced therapy response observed when initiating treatment during dioestrus. Our data collectively demonstrate the oestrous cycle as a crucial infradian rhythm determining chemosensitivity, warranting future clinical studies to exploit optimal treatment initiation timing for enhanced chemotherapy outcomes.

DOI: 10.1038/s41586-024-08276-1

Source: https://www.nature.com/articles/s41586-024-08276-1