CKAP4, a DKK1 Receptor, Is a Biomarker in Exosomes Derived from Pancreatic Cancer and a Molecular Target for Therapy
CKAP4, a DKK1 Receptor, Is a Biomarker in Exosomes Derived from Pancreatic Cancer and a Molecular Target for Therapy
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DOI：
10.1158/1078-0432.ccr-18-2124
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发表时间：
2019-03-15
影响因子：
11.5
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
--
作者：
Kimura, Hirokazu;Yamamoto, Hideki;Kikuchi, Akira
目的：胰腺导管腺癌（PDAC）的生存率很低，因此，需要新的分子靶向治疗和伴随诊断。我们问是否细胞凋亡相关蛋白4（CKAP 4），一种新的Dickkopf1（DKK 1）受体，是一个候选人PDAC的诊断和therapeutic设计：是否CKAP 4可以分泌小细胞外囊泡（SEV）从PDAC细胞进行了检查。结果：PDAC细胞分泌CKAP 4，其SEV具有exosomes的特征。含有CKAP 4的外泌体的分泌由DKK 1依赖性内吞途径介导，并且需要外泌体生物发生分子。开发了两种能够检测肿瘤分泌的CKAP 4的ELISA。PDAC患者血清CKAP 4水平高于健康对照组。CKAP 4在胰腺肿瘤荷瘤异种移植小鼠和PDAC患者的血清中高度检测到，而CKAP 4在正常小鼠和术后患者的血清中几乎检测不到。不同表位的抗CKAP 4单克隆抗体对DKK 1和CKAP 4的结合、AKT活性以及PDAC细胞的增殖和迁移均有抑制作用。抗CKAP 4单克隆抗体也抑制了免疫缺陷小鼠的异种移植瘤形成，并延长了接受腹膜内或原位注射PDAC cells.Conclusions的小鼠的生存期：CKAP 4分泌在外泌体中可能代表PDAC的生物标志物。抗CKAP 4单克隆抗体有助于开发新的诊断方法和治疗方法。
Purpose: The survival rate of pancreatic ductal adenocarcinoma (PDAC) is poor; thus, novel molecularly targeted therapy and companion diagnostics are required. We asked whether cytoskeleton-associated protein 4 (CKAP4), a novel Dickkopf1 (DKK1) receptor, is a candidate for PDAC diagnosis and therapy.Experimental Design: Whether CKAP4 can be secreted with small extracellular vesicles (SEV) from PDAC cells was examined. It was also investigated whether CKAP4 can be detected in sera from patients with PDAC by ELISA using newly generated anti-CKAP4 mAbs and whether anti-CKAP4 mAbs can show antitumor activity in vivo.Results: CKAP4 was secreted with SEVs from PDAC cells, and the SEVs exhibited the characteristics of exosomes. The secretion of CKAP4-containing exosomes was mediated by DKK1-dependent endocytosis routes and required exosome biogenesis molecules. Two ELISAs capable of detecting tumor-secreted CKAP4 were developed. The serum CKAP4 levels were higher in patients with PDAC than healthy control individuals. CKAP4 was highly detected in the sera of pancreatic tumor-bearing xenografted mice and patients with PDAC, whereas CKAP4 was barely detectable in sera from normal mice and postoperative patients. Anti-CKAP4 mAbs with different epitopes demonstrated the inhibitory activities for the binding of DKK1 and CKAP4, AKT activity, and proliferation and migration of PDAC cells. Anti-CKAP4 mAbs also suppressed xenograft tumor formation in immunodeficient mice and extended the survival of mice receiving intraperitoneal or orthotopic injection of PDAC cells.Conclusions: CKAP4 secreted in exosomes may represent a biomarker for PDAC. Anti-CKAP4 mAbs can contribute to the development of novel diagnostic methods and therapeutics.