Matsuda Yoko, Yoshimura Hisashi, Ueda Junji, Naito Zenya, Korc Murray, Ishiwata Toshiyuki
Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan; Department of Surgery for Organ and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Am J Pathol. 2014 Mar;184(3):674-85. doi: 10.1016/j.ajpath.2013.11.014. Epub 2014 Jan 9.
Pancreatic ductal adenocarcinoma (PDAC) is associated with a high incidence of hepatic metastases, as well as occasional pulmonary metastases. To delineate the potential role of cancer stem cells (CSCs) in PDAC metastasis, human PDAC cells were injected into the spleen of mice. The characteristics and expression of markers associated with CSC and epithelial-mesenchymal transition (EMT) of metastatic cells that developed in the liver and lung were then compared with parental cells. The metastatic cells were polygonal, and larger than parental cells. Metastatic cells also exhibited decreased proliferation and increased adhesion to extracellular matrices, as well as enhanced migration and invasion in vitro and increased metastatic capacity in vivo. The CSC markers ALDH1A1, ABCG2, and nestin were expressed at high levels in metastatic cells and exhibited changes consistent with EMT (eg, decreased E-cadherin expression). Moreover, metastatic cells readily formed spheres in culture and exhibited an increased side population by flow analysis. Nestin and ABCG2 were also expressed at high levels in metastatic lesions from PDAC patients, and silencing nestin with shRNA in PDAC cells derived from lung metastases resulted in a marked decrease in the capacity of the cells to form spheres and to yield pulmonary or hepatic metastases. Thus, the metastatic potential of human PDAC cells correlates with CSCs and with EMT characteristics and is dependent on nestin expression.
胰腺导管腺癌（PDAC）与肝转移的高发生率相关，也偶有肺转移。为了阐明癌症干细胞（CSC）在PDAC转移中的潜在作用，将人PDAC细胞注射到小鼠脾脏中。然后将在肝脏和肺中形成的转移性细胞的与CSC及上皮-间质转化（EMT）相关的标志物的特征和表达与亲代细胞进行比较。转移性细胞呈多边形，比亲代细胞大。转移性细胞还表现出增殖减少、对细胞外基质的黏附增加、体外迁移和侵袭增强以及体内转移能力增加。CSC标志物醛脱氢酶1A1（ALDH1A1）、ATP结合盒转运蛋白G2（ABCG2）和巢蛋白在转移性细胞中高水平表达，并表现出与EMT一致的变化（例如，E-钙黏蛋白表达降低）。此外，转移性细胞在培养中易于形成球体，并且通过流式分析显示侧群增加。巢蛋白和ABCG2在PDAC患者的转移灶中也高水平表达，并且在源自肺转移的PDAC细胞中用短发夹RNA（shRNA）沉默巢蛋白导致细胞形成球体以及产生肺或肝转移的能力显著降低。因此，人PDAC细胞的转移潜能与CSC以及EMT特征相关，并且依赖于巢蛋白的表达。
