膵発がん幹細胞候補の同定

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  • 津田 洋幸
    名古屋市立大学大学院医学研究科分子毒性学分野
  • 深町 勝巳
    名古屋市立大学大学院医学研究科分子毒性学分野
  • 徐 結苟
    名古屋市立大学大学院医学研究科分子毒性学分野
  • ALEXANDER David B.
    <I>Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences</I>
  • 上田 しのぶ
    名古屋市立大学大学院医学研究科分子毒性学分野 国立がんセンター研究所がん転移研究室
  • 田中 創始
    名古屋市立大学大学院医学研究科臨床機能内科分野
  • 林 香月
    名古屋市立大学大学院医学研究科臨床機能内科分野
  • 落谷 孝広
    国立がんセンター研究所がん転移研究室
  • 斉藤 泉
    東京大学医科学研究所遺伝子解析施設

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タイトル別名
  • Identification of Cancer Stem Cell Candidates of Pancreatic Ductal Carcinoma

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Pancreatic ductal adenocarcinoma is one of the most debilitating malignancies in humans with median survival times after treatment being less than 12 months. For the improvement of survivals, development of appropriate animal models which biologically mimic the human lesion is urgently required. Recent studies indicated that biological characteristics of tumor is dependent on cells in which a tumor grows, termed cancer stem cells. Although the data have been provided to support this theory in human tumors of blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Although, pancreas ductal carcinomas were induced by induction of activated K-ras gene into the precursor gene in mouse, the responsible cells are not directly indicated. We conducted the study to determine if targeted activation of a human oncogenic-ras transgene in rat fully developed pancreas cell would induce carcinomas correspondent to human pancreatic ductal adenocarcinomas. Thus, transgenic (Hras250) rats in which expression of a human Ha-rasG12V oncogene is regulated by the Cre/lox system is established. Targeted pancreatic activation of the transgene was accomplished by injection of Cre carrying adenovirus into the pancreatic ducts and acini through the common bile duct. Adenoviral infection of injected animals was exclusive to the pancreas; infected cells could be identified in duct, intercalated duct, centroacinar, and, less frequently, acinar cells, but not in endocrine islet cells. Four weeks after injection, proliferative lesions were exclusively observed in the duct epithelium, intercalated ducts, and centroacinar cells, but not acinar cells. Most lesions, including atypical duct proliferative lesions, PanIN-like lesions, and carcinomas, were positive for cyokeratins 19 and 7, cyclooxigenase 2, and MMP-7 but negative for amylase and chymotrypsin. Many adenocarcinoma lesions were positive for EGF and EGFR. Duct epithelial and atypical duct proliferative lesions and carcinoma lesions were all positive for transduced Ha-rasG12V oncogene expression. This model exhibits close similarities to the human lesions and promises to advance our understanding of biological characteristics of pancreas adenocarcinomas. Results indicate that pancreatic duct epithelium, intercalated duct cells and centroacinar cells are possible candidate of cancer stem cells pancreas duct carcinomas.

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