title: Nestin delineates pancreatic cancer stem cells in metastatic foci of NOD/Shi-scid IL2Rγ(null) (NOG) mice.
abstract: 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.
authors.affiliation: Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yoshimura
authors.affiliation: 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.
authors.forename: Junji
authors.initials: J
authors.lastname: Ueda
authors.affiliation: Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
authors.forename: Zenya
authors.initials: Z
authors.lastname: Naito
authors.affiliation: Departments of Medicine and Biochemistry and Molecular Biology, Indiana University School of Medicine and the Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
authors.affiliation: Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan. Electronic address: ishiwata@nms.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishiwata
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*; D064231:Nestin / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D064231:Nestin; D034741:RNA, Small Interfering