瑞士肿瘤研究所Andrea Alimonti小组发现，凝血因子X促进前列腺癌对雄激素剥夺治疗的耐受。这一研究成果于2024年9月19日在线发表在国际学术期刊《癌细胞》上。

通过对小鼠去势抵抗性前列腺癌（CRPC）模型的前列腺肿瘤微环境（TME）进行单细胞RNA测序（scRNA-seq），研究人员发现免疫抑制性中性粒细胞（PMN-MDSC）是肝外凝血因子X（FX）的关键来源。

TME中的FX激活通过激活蛋白酶激活受体2（PAR2）和肿瘤细胞中ERK1/2的磷酸化，增强雄激素非依赖性肿瘤生长。

对凝血因子Xa（FXa）的基因和药理学抑制可对抗PMN-MDSCs的致癌活性，减少肿瘤进展，并与恩杂鲁胺治疗产生协同作用。

有趣的是，F10高表达的PMN-MDSC表达表面标志物CD84，且CD84的结合可增强F10的表达。在CRPC患者中，前列腺肿瘤中FX、CD84和PAR2的高水平与更差的生存率相关。

该研究提供了FXa直接促进癌症的证据，并强调了针对PMN-MDSC的额外癌症治疗靶点。

据悉，尽管高凝状态通常与恶性肿瘤相关，但凝血因子是否直接影响肿瘤细胞增殖仍不明确。

附：英文原文

Title: Coagulation factor X promotes resistance to androgen-deprivation therapy in prostate cancer

Author: Bianca Calì, Martina Troiani, Silvia Bressan, Giuseppe Attanasio, Sara Merler, Viola Moscarda, Simone Mosole, Elena Ricci, Christina Guo, Wei Yuan, Lewis Gallagher, Arian Lundberg, Ilona Bernett, Ines Figueiredo, Rydell Alvarez Arzola, Ernesto Bermudez Abreut, Mariantonietta D’Ambrosio, Nicolò Bancaro, Daniela Brina, Sara Zumerle, Emiliano Pasquini, Martino Maddalena, Ping Lai, Manuel Colucci, Nicolò Pernigoni, Andrea Rinaldi, Davide Minardi, Alessandro Morlacco, Fabrizio Dal Moro, Marianna Sabbadin, Francesca Galuppini, Matteo Fassan, Jan Hendrik Rüschoff, Holger Moch, Pasquale Rescigno, Edoardo Francini, Calogero Saieva, Mikol Modesti, Jean-Philippe Theurillat, Silke Gillessen, Petra Wilgenbus, Claudine Graf, Wolfram Ruf, Johann de Bono, Andrea Alimonti

Issue&Volume: 2024-09-19

Abstract: Although hypercoagulability is commonly associated with malignancies, whether coagulation factors directly affect tumor cell proliferation remains unclear. Herein, by performing single-cell RNA sequencing (scRNA-seq) of the prostate tumor microenvironment (TME) of mouse models of castration-resistant prostate cancer (CRPC), we report that immunosuppressive neutrophils (PMN-MDSCs) are a key extra-hepatic source of coagulation factor X (FX). FX activation within the TME enhances androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells. Genetic and pharmacological inhibition of factor Xa (FXa) antagonizes the oncogenic activity of PMN-MDSCs, reduces tumor progression, and synergizes with enzalutamide therapy. Intriguingly, F10high PMN-MDSCs express the surface marker CD84 and CD84 ligation enhances F10 expression. Elevated levels of FX, CD84, and PAR2 in prostate tumors associate with worse survival in CRPC patients. This study provides evidence that FXa directly promotes cancer and highlights additional targets for PMN-MDSCs for cancer therapies.

DOI: 10.1016/j.ccell.2024.08.018

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00317-9