Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer.
Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer.
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DOI：
10.1126/scisignal.aaa5823
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发表时间：
2015-08-04
影响因子：
7.3
通讯作者：
Zheng L
中科院分区：
文献类型：
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作者：
Foley K;Rucki AA;Xiao Q;Zhou D;Leubner A;Mo G;Kleponis J;Wu AA;Sharma R;Jiang Q;Anders RA;Iacobuzio-Donahue CA;Hajjar KA;Maitra A;Jaffee EM;Zheng L
大多数胰腺导管腺癌（PDA）患者在诊断时存在转移性疾病，或在手术治疗后复发并转移。在发育过程中信号通路介导了神经轴突的迁移和血管生成过程中的血管迁移。编码信号蛋白3D （Sema3D）的基因在PDA肿瘤中表达增加，一些PDA手术切除后患者血清中存在针对多效蛋白膜联蛋白A2 （AnxA2）的抗体，这与更长的无复发生存期有关。通过在PDA转基因小鼠模型（KPC）中敲除AnxA2，我们发现AnxA2促进了体内转移，该模型再现了人类PDA从恶性前病变到转移疾病的进展。表达AnxA2可促进PDA细胞分泌Sema3D，并与共受体丛蛋白D1 （PlxnD1）在PDA细胞上共免疫沉淀。SEMA3D敲除或anxa2缺失的小鼠PDA细胞在培养和小鼠中表现出侵袭性和转移性降低的潜力。然而，在没有AnxA2的细胞中恢复Sema3D并不能完全挽救培养和体内的转移行为，这表明AnxA2介导了其他的促转移机制。与Sema3D丰度相对较低的肿瘤患者相比，具有丰富Sema3D的原发性PDA肿瘤患者具有广泛的转移性疾病，并且生存率降低。因此，AnxA2和Sema3D可能是转移性PDA的新的治疗靶点和预后标志物。
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.