Determination of cancer stem cells and evaluation for cancer immunotherapy against cancer stem cells

• Project/Area Number: 24590498
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Institute of Advanced Industrial Science and Technology
• Principal Investigator: IKEHARA YUZURU 独立行政法人産業技術総合研究所, バイオメデイカル研究部門, 上級主任研究員 (10311440)
• Co-Investigator(Renkei-kenkyūsha): YAMAGUCHI Takashi 独立行政法人産業技術総合研究所, バイオメデイカル研究部門, 契約職員 (60626563)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 膵臓がん / がん幹細胞 / 細胞分化 / 免疫治療 / 腺管構造の形成 / 幹細胞Sphere / 免疫応答 / T抗原エピトープ / マウスモデル / 三次元培養 / 不死化 / 幹細胞 / 腫瘍

Outline of Final Research Achievements

This study was conducted to increase knowledge about nature of stem cells in CK19+ pancreatic ductal epithelial cells. Established mouse pancreatic cancer and immortalized cell lines with CK19+ formed sphere structure (SS) and tubular structure (TS) in three dimension culture using collagen gels. We have demonstrated that there were differential types of stem cells in SS and TS, and presence of the cells determines SS and TS, respectively. Additionally, TGFβ and the signal transduction pathway was identified to promote from SS to TS conversion. Furthermore, immune reaction could control cancer cells growth of both SS and TS, while rejection of tumor cells was impaired by tolerance linked with CD4+CD25+regulatory T cells and monocyte with CD11b+ /F4/80+.
In conclusion, though ｔhere are different types of stem cells in pancreatic cancer, immune therapy is feasible to use for control over the differentiation status.

Research Products

• [Journal Article] Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case (2015)
  • Author(s): Saito T, Kondo C, Shitara K, Ito Y, Saito N, Ikehara Y, Yatabe Y, Yamamichi K, Tanaka T, Nakanishi H
  • Journal Title: Pathol Int Volume: 印刷中 Issue: 6 Pages: 309-317
  • DOI: 10.1111/pin.12290
  • Peer Reviewed / Open Access
• [Journal Article] Glycoproteomics approach for identifying Glycobiomarker candidate molecules for tissue type classification of non-small cell lung carcinoma. (2014)
  • Author(s): Hirao Y, Matsuzaki H, Iwaki J, Kuno A, Kaji H, Ohkura T, Togayachi A, Abe M, Nomura M, Noguchi M, Ikehara Y, Narimatsu H
  • Journal Title: J Proteome Res Volume: 13(11) Issue: 11 Pages: 4705-4716
  • DOI: 10.1021/pr5006668
  • Peer Reviewed
• [Journal Article] A genetically engineered mouse model developing rapid progressive pancreatic ductal adenocarcinoma (2014)
  • Author(s): Yamaguchi T, Ikehara S, Nakanishi H, IkeharaY
  • Journal Title: The Journal of Pathology Volume: 234(2) Issue: 2 Pages: 228-238
  • DOI: 10.1002/path.4402
  • Peer Reviewed / Open Access
• [Journal Article] Mice lacking α1,3-fucosyltransferase 9 exhibit modulation of in vivo immune responses against pathogens (2014)
  • Author(s): Kashiwazaki H, Kakizaki M, Ikehara Y, Togayachi A, Narimatsu H, Watanabe R
  • Journal Title: Pathol Int Volume: 64(5) Issue: 5 Pages: 199-208
  • DOI: 10.1111/pin.12159
  • Peer Reviewed
• [Journal Article] Synthesis and evaluation of a radioiodinated peptide probe targeting αvβ6 integrin for the detection of pancreatic ductal adenocarcinoma (2014)
  • Author(s): Ueda M, Fukushima T, Ogawa K, Kimura H, Ono M, Yamaguchi T, Ikehara Y, Saji H
  • Journal Title: Biochem Biophys Res Commun Volume: 445(3) Issue: 3 Pages: 661-666
  • DOI: 10.1016/j.bbrc.2014.02.086
  • NAID: 120005466666
  • Peer Reviewed / Open Access
• [Journal Article] Novel glycobiomarker for ovarian cancer that detects clear cell carcinoma. (2014)
  • Author(s): Sogabe M, Nozaki H, Tanaka N, Kubota T, Kaji H, Kuno A, Togayachi A, Gotoh M, Nakanishi H, Nakanishi T, Mikami M, Suzuki N, Kiguchi K, Ikehara Y, Narimatsu H
  • Journal Title: J Proteome Res Volume: 7 Issue: 3 Pages: 1624-1635
  • DOI: 10.1021/pr401109n
  • Peer Reviewed / Open Access
• [Journal Article] 糖鎖情報から読み解く，生命活動と病理. (2014)
  • Author(s): 池原 譲
  • Journal Title: 病理と臨床 Volume: 32(6) Pages: 677-681
• [Journal Article] 出血制御における従来手法と低温プラズマ法の比較. (2014)
  • Author(s): 池原 譲
  • Journal Title: 静電気学会雑誌 Volume: 38(4) Pages: 171-176
• [Journal Article] Application of a Glycoproteomics-Based Biomarker Development Method: Alteration in Glycan Structure on Colony Stimulating Factor 1 Receptor as a Possible Glycobiomarker Candidate for Evaluation of Liver Cirrhosis. (2014)
  • Author(s): 32) Ocho M, Togayachi A, Iio E, Kaji H, Kuno A, Sogabe M, Korenaga M, Gotoh M, Tanaka Y, Ikehara Y, Mizokami M, Narimatsu H.
  • Journal Title: J Proteome Res. Volume: 13(3) Issue: 3 Pages: 1428-1437
  • DOI: 10.1021/pr400986t
  • Peer Reviewed
• [Journal Article] Immunoassay with single-walled carbon nanotubes as near-infrared fluoresent labels (2013)
  • Author(s): Yoko Iizumi, Toshiya Okazaki, Yuzuru Ikehara, Mutsuo Ogura, Shisuke Fukada, Masako Yudasaka
  • Journal Title: Appl. Mater. & Interfaces Volume: 5 Issue: 16 Pages: 7665-7670
  • DOI: 10.1021/am401702q
  • Peer Reviewed
• [Journal Article] Clgalt1-deficient mice exhibit thrombocytopenia due to abnormal terminal differentiation of megakaryocytes (2013)
  • Author(s): Kudo T, et al. (13人中8番目)
  • Journal Title: Blood Volume: 122 Issue: 9 Pages: 1649-1657
  • DOI: 10.1182/blood-2012-12-471102
  • Peer Reviewed
• [Journal Article] Podocalyxin Is a Glycoprotein Ligand of the Human Pluripotent Stem Cell-Specific ProberBC2LCN. (2013)
  • Author(s): Tateno H, Matsushima A, Hiemori K, Onuma Y, Ito Y, Hasehira K, Nishimura K,Ohtaka M, Takayasu S, Nakanishi M, Ikehara Y,Nakanishi M, Ohnuma K, Chan T,Toyoda M, Akutsu H, Umezawa A, Asashima M, Hirabayashi J.
  • Journal Title: Stem Cells Transl Med. Volume: 2(4) Issue: 4 Pages: 265-273
  • DOI: 10.5966/sctm.2012-0154
  • Peer Reviewed
• [Journal Article] Glycoproteomics-based cancer marker discovery adopting dual enrichment with Wisteria floribunda agglutinin for high specific glyco-diagnosis of cholangiocarcinoma. (2013)
  • Author(s): Matsuda A, Kuno A, Matsuzaki H, Kawamoto T, Shinkai T, Nakanuma Y, Yamamoto M, Ohkohchi N, Ikehara Y, Shoda J, Hirabayashi J, Narimatsu H
  • Journal Title: J Proteomics Volume: 85 Pages: 1-11
  • DOI: 10.1016/j.jprot.2013.04.017
  • Peer Reviewed
• [Journal Article] Different levels of Sialyl-Tn Antigen expressed on MUC16 in Patients With Endometriosis and Ovarian Cancer (2012)
  • Author(s): Akita K
  • Journal Title: Int J Gynecol Cancer Volume: VOL.22(4) Issue: 4 Pages: 531-8
  • DOI: 10.1097/igc.0b013e3182473292
  • Peer Reviewed
• [Journal Article] PCR Detection of Babesia ovata from Cattle Reared in Japan and Clinical Significance of Co-Infection with Theileria orientalis (2012)
  • Author(s): Sivakumar, T., Tagawa, M., Yoshinari, T., Ybanez, A. P., Igarashi, I., Ikehara, Y., Hata, H., Kondo, S., Matsumoto, K., Inokuma, H., and Yokoyama, N
  • Journal Title: J. Clin. Microbiol Volume: 50 Issue: 6 Pages: 2111-3
  • DOI: 10.1128/jcm.00220-12
  • Peer Reviewed
• [Journal Article] Establishment and characterization of novel gastric signet-ring cell and non signet-ring cell, poorly-differentiated adenocarcinoma cell lines with low and high malignant potential (2012)
  • Author(s): Murakami H, Nakanishi H, Tanaka H, Ito S, Misawa K, Ito Y, Ikehara Y, Kondo E, Kodera Y.
  • Journal Title: Gastric Cancer Volume: (in press) Issue: 1 Pages: 74-83
  • DOI: 10.1007/s10120-012-0149-2
  • NAID: 40019557355
  • Peer Reviewed
• [Journal Article] LecT-Hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients (2012)
  • Author(s): Ito K, Kuno A, Ikehara Y, Sugiyama M, Saito H, Aoki Y, Matsui T, Imamura M, Korenaga M, Murata K, Masaki N, Tanaka Y, Hige S, Izumi N, Kurosaki M, Nishiguchi S, Sakamoto M, Kage M, Narimatsu H, Mizokami M
  • Journal Title: Hepatology Volume: 56 Issue: 4 Pages: 1448-56
  • DOI: 10.1002/hep.25815
  • Peer Reviewed
• [Journal Article] Comparison of LecT-Hepa and FibroScan for assessment of liver fibrosis in hepatitis B virus infected patients with different ALT levels. (2012)
  • Author(s): DU Dongning
  • Journal Title: Clin Chim Acta Volume: 413 Issue: 21-22 Pages: 21-22
  • DOI: 10.1016/j.cca.2012.07.005
  • Peer Reviewed
• [Presentation] Feasibility and expanding roles of plasma coagulation technology to improve the prognosis of pancreatic cancer (2015)
  • Author(s): Yuzuru Ikehara
  • Organizer: IWPCT2015
  • Place of Presentation: 名古屋大学
  • Year and Date: 2015-03-16 – 2015-03-17
  • Invited
• [Presentation] 糖鎖情報で読み解く、組織病理の世界 (2014)
  • Author(s): 池原 譲
  • Organizer: 第55回日本組織細胞化学会
  • Place of Presentation: 松本市公民館
  • Year and Date: 2014-09-28
• [Presentation] グライコプロテオーム解析によるがんマーカーの開発 (2014)
  • Author(s): 池原 譲, 成松 久
  • Organizer: 第73回日本癌学会学術総会 JCA-JSP Joint Symposium.
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-26 – 2014-09-28
• [Presentation] プラズマによる低侵襲止血が牽引する、すい臓がん克服のための診断治療技術の学際的研究開発 (2014)
  • Author(s): 池原 譲
  • Organizer: 新学術領域研究「プラズマ医療科学の創成」第3回公開シンポジウム
  • Place of Presentation: 名古屋大学
  • Year and Date: 2014-08-09
  • Invited
• [Presentation] An application of low temperature plasma to achieve minimal invasive surgery (2014)
  • Author(s): Yuzuru Ikehara
  • Organizer: 5th International Conference on Plasma Medicine (ICPM5)
  • Place of Presentation: Nara Prefectural New Public Hall
  • Year and Date: 2014-05-18 – 2014-05-23
  • Invited
• [Presentation] 3 次元培養法を用いたTGF-β による膵管上皮細胞の分化制御メカニズムの検討. (2014)
  • Author(s): 山口高志, 池原早苗, 中西速夫, 池原譲
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 波長1.2-2 μm を捉える近赤外イメージングの開発とマクロ病理学への展開 (2014)
  • Author(s): 池原 譲
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] A clinical need for medical plasma equipment in line with progression of minimally invasive surgical procedure. (2014)
  • Author(s): Yuzuru Ikehara, Hajime Sakakita, Nobuyuki Shimizu, Sanae Ikehara, Hayao Nakanishi
  • Organizer: 8th International Conference on Reactive Plasmas/31st Symposium on Plasma Processing (ICRP8/SPP-31)Fukuoka
  • Place of Presentation: 福岡国際会議場
  • Invited
• [Presentation] De novo 膵臓発がんモデルを用いたがん幹細胞と幹細胞ニッチの解析 (2013)
  • Author(s): 池原 譲、山口 高志、池原早苗
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: ロイトン札幌/さっぽろ芸文館
• [Presentation] A genetically engineered mouse model of de novo pancreatic carcinogenesis (2013)
  • Author(s): Takashi Yamaguchi, Sanae K. Ikehara, Yuzuru Ikehara
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington, D.C
• [Presentation] 硫酸化糖鎖の発現亢進によるホルモン不応答性前立腺癌増殖メカニズムと、その糖鎖バイオマーカーの可能性 (2013)
  • Author(s): 佐々木正雄、池原譲、佐藤慎哉、澤木弘道、平野和己、Toin H. van kuppevelt、中西速夫、西原祥子、成松久
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: ロイトン札幌/さっぽろ芸文館
• [Presentation] 低侵襲性医療の実現に向けたプラズマ止血デバイスへの期待 -医療用マイルドプラズマによる創傷治癒の確立とプラズマ－組織細胞交互作用の解明 (2013)
  • Author(s): 池原 譲
  • Organizer: 文部科学省科学研究費新学術領域「プラズマ医療科学の創成」公開シンポジウム
  • Place of Presentation: 名古屋大学
  • Invited
• [Presentation] プラズマによる低侵襲の出血制御および、プラズマ処置で生じる血液凝固物の創傷被覆材としての意義について. (2013)
  • Author(s): 池原 譲
  • Organizer: 30th International Conference of Photopolymer Science and Technology (ICPST-30)
  • Place of Presentation: 千葉大学
  • Invited
• [Presentation] Meanings of glycobiological approaches to detect diseases
  • Author(s): Ikehara Y
  • Organizer: Tsukuba Nanotechnology Symposium 2012
  • Place of Presentation: Tsukuba, Japan
  • Invited
• [Presentation] Evaluation for ductal phenotype of mouse pancreatic ductal adenocarcinoma (PDAC) and the immortalized pancreatic ductal cells.
  • Author(s): Yamaguchi T., Ikehara S., Nakanishi H., Ikehara Y.
  • Organizer: 14th, Int. Natl. Cong. of Histochem. Cytochem.
  • Place of Presentation: Kyoto, Japan
• [Presentation] 生物機能と疾患の理解を目指した糖鎖生物学研究
  • Author(s): 池原 譲
  • Organizer: 第58回日本病理学会秋季特別総会
  • Place of Presentation: 東京
• [Presentation] PathophysiologicalMeanings of PlasmaTreatment for Blood Bleeding and the Wound HealingProcess
  • Author(s): Ikehara Y* and Sakakita H.
  • Organizer: Material Research Society 2012 Spring Meeting and Exhibition, 2012
  • Place of Presentation: San Francisco, USA
  • Invited
• [Presentation] Plasma Physics and Its global Applications
  • Author(s): Sakakita H and Ikehara Y
  • Organizer: Material Research Society 2012 Spring Meeting and Exhibition, 2012
  • Place of Presentation: San Francisco, USA
  • Invited
• [Book] Mouse Models of Cancer. In: Glycoscience: Biology and Medicine. Edited by Taniguchi N, Endo T, and Hart GW. (2014)
  • Author(s): Ikehara Y, Yamaguchi T, Ikehara S.
  • Publisher: Springer Reference.
• [Patent(Industrial Property Rights)] 撮像システム及び撮像方法 (2013)
  • Inventor(s): 池原 譲、小倉 睦郎、牧野内 進
  • Industrial Property Rights Holder: 産業技術総合研究所、株式会社ニコン
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-113825
  • Filing Date: 2013-05-28
• [Patent(Industrial Property Rights)] 糖鎖アイソフォーム検出方法及び糖鎖アイソフォーム検出装置 (2013)
  • Inventor(s): 成松久、久野敦、池原譲、ほか4名
  • Industrial Property Rights Holder: 成松久、久野敦、池原譲、ほか4名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-08-09
  • Overseas