Foley Kelly, Rucki Agnieszka A, Xiao Qian, Zhou Donger, Leubner Ashley, Mo Guanglan, Kleponis Jennifer, Wu Annie A, Sharma Rajni, Jiang Qingguang, Anders Robert A, Iacobuzio-Donahue Christine A, Hajjar Katherine A, Maitra Anirban, Jaffee Elizabeth M, Zheng Lei
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sci Signal. 2015 Aug 4;8(388):ra77. doi: 10.1126/scisignal.aaa5823.
Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin-plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive and metastatic potential in culture and in mice. However, restoring Sema3D in AnxA2-null cells did not entirely rescue metastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively low Sema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.
大多数胰腺导管腺癌（PDA）患者在诊断时就已出现转移性疾病，或在手术治疗后会复发并伴有转移。信号素-丛蛋白信号传导在发育过程中介导神经元轴突的迁移，在血管生成过程中介导血管的迁移。编码信号素3D（Sema3D）的基因在PDA肿瘤中的表达增加，在部分PDA患者手术切除后的血清中存在针对多效性蛋白膜联蛋白A2（AnxA2）的抗体与更长的无复发生存期相关。通过在一种模拟人类PDA从癌前病变发展到转移性疾病进程的PDA转基因小鼠模型（KPC）中敲除AnxA2，我们发现AnxA2在体内促进转移。AnxA2的表达促进了PDA细胞分泌Sema3D，Sema3D与PDA细胞上的共受体丛蛋白D1（PlxnD1）共免疫沉淀。敲低SEMA3D的小鼠PDA细胞或AnxA2基因缺失的PDA细胞在培养物中和小鼠体内均表现出侵袭和转移潜能降低。然而，在AnxA2基因缺失的细胞中恢复Sema3D并不能完全挽救其在培养物中和体内的转移行为，这表明AnxA2介导了其他促转移机制。与Sema3D丰度相对较低的肿瘤患者相比，原发性PDA肿瘤中Sema3D丰富的患者具有广泛的转移性疾病且生存率降低。因此，AnxA2和Sema3D可能是转移性PDA的新治疗靶点和预后标志物。
