Development of cancer stem cells driven by microenvironment

• Project/Area Number: 26670023
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Juntendo University (2015-2017); St. Luke's International University (2014)
• Principal Investigator: IRIMURA Tatsuro 順天堂大学, 医学部, 特任教授 (80092146)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん幹細胞 / ZnT1 / モノクローナル抗体 / 大腸がん / 乳がん / フローサイトメトリー / 非対称分裂 / ZnT1、、非対称分裂 / モのクロ－ナル抗体

Outline of Final Research Achievements

Cancer stem cells are important subjects to understand the treatment resistance, latency and recurrence of cancer and to improve therapy. However, it was not easy to identify them in histological and cytological context. The mechanism how they give rise should be investigated with appropriate surface markers, which was not available. We have recently prepared a monoclonal antibody against ZnT1, a cancer stem cell surface marker candidate discovered by genetic analysis. Our specific aim was to visualize the developmental state of cancer stem cells by the use of the antibody. However, after careful investigations conducted under the present project, we concluded that the anti-ZnT1 antibody positive cell population was not identical to cancer stem cell populations identified by other methods. The expression status of this molecule did not correlate with the treatment resistance of cancer. However, we found that the developed monoclonal antibody is useful as a tool to analyze ZnT1.

Research Products

• [Int'l Joint Research] Jagiellonian University(Poland)
• [Int'l Joint Research] UT-MD Anderson Cancer Center(米国)
• [Journal Article] Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology. (2018)
  • Author(s): Adachi H, Nakae K, Sakamoto S, Nosaka C, Atsumi S, Shibuya M, Higashi N, Nakajima M, Irimura T, Nishimura Y.
  • Journal Title: J Antibiot (Tokyo). Volume: 71 Issue: 1 Pages: 60-71
  • DOI: 10.1038/ja.2017.138
  • Peer Reviewed
• [Journal Article] A Critical Domain of Ebolavirus Envelope Glycoprotein Determines Glycoform and Infectivity (2018)
  • Author(s): Fujihira H, Usami K, Matsuno K, Takeuchi H, Denda-Nagai K, Furukawa JI, Shinohara Y, Takada A, Kawaoka Y, Irimura T
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 5495-5495
  • DOI: 10.1038/s41598-018-23357-8
  • Peer Reviewed / Open Access
• [Journal Article] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition" (2017)
  • Author(s): Hailiang Wu, Anqi Tao, John D. Martin, Sabina Quader, Xueying Liu, Kei Takahashi, Louise Hespel, Yutaka Miura, Yoshihiro Hayakawa, Tatsuro Irimura, Horacio Cabral, Kazunori Kataoka
  • Journal Title: J. Pharm. Sci, Volume: - Issue: 9 Pages: 30217-30224
  • DOI: 10.1016/j.xphs.2017.03.031
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression. (2016)
  • Author(s): Kimura Y, Nagai N, Tsunekawa N, Sato-Matsushita M, Yoshimoto T, Cua DJ, Iwakura Y, Yagita H, Okada F, Tahara H, Saiki I, Irimura T, Hayakawa Y.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 9 Pages: 1206-14
  • DOI: 10.1111/cas.13005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An iminosugar-based heparanase inhibitor heparastatin (SF4) suppresses infiltration of neutrophils and monocytes into inflamed dorsal air pouches. (2016)
  • Author(s): Sue M, Higashi N, Shida H, Kogane Y, Nishimura Y, Adachi H, Kolaczkowska E, Kepka M, Nakajima M, Irimura T.
  • Journal Title: Int Immunopharmacol Volume: 35 Pages: 15-21
  • DOI: 10.1016/j.intimp.2016.03.017
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Report on the use of nonclinical studies in the regulatory evaluation of oncology drugs (2016)
  • Author(s): Hayakawa Y, Kawada M, Nishikawa H, Ochiya T, Saya H, Seimiya H, Yao Y, Hayashi M, Kai C, Matsuda A, Naoe T, Ohtsu A, Okazaki T, Saji H, Sata M, Sugimura H, Sugiyama Y, Toi M, Irimura T
  • Journal Title: Cancer Sci Volume: 107(2) Issue: 2 Pages: 189-202
  • DOI: 10.1111/cas.12857
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Heparanase augments inflammatory chemokine production from colorectal carcinoma cell lines. (2016)
  • Author(s): Tsunekawa N, Higashi N, Kogane Y, Waki M, Shida H, Nishimura Y, Adachi H, Nakajima M, Irimura T
  • Journal Title: Biochem Biophys Res Commun Volume: 469 Issue: 4 Pages: 878-883
  • DOI: 10.1016/j.bbrc.2015.12.074
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mammary tissue microenvironment determines T cell-dependent breast cancer-associated inflammation. (2015)
  • Author(s): Takahashi K, Nagai N, Ogura K, Tsuneyama K, Saiki I, Irimura T, Hayakawa Y.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 7 Pages: 867-874
  • DOI: 10.1111/cas.12685
  • NAID: 120006389612
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Viwatthanasittiphong C, Srivatanakul P, Miwa M, Shoda J, Narimatsu H. Lectin Microarray-Based Sero-Biomarker Verification Targeting Aberrant O-Linked Glycosylation on Mucin 1. (2015)
  • Author(s): Matsuda A, Kuno A, Nakagawa T, Ikehara Y, Irimura T, Yamamoto M, Nakanuma Y, Miyoshi E, Nakamori S, Nakanishi H.
  • Journal Title: Anal Chem. Volume: 87(14) Issue: 14 Pages: 7274-7281
  • DOI: 10.1021/acs.analchem.5b01329
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] POMGNT1 Is Glycosylated by Mucin-Type <i>O</i>-Glycans (2015)
  • Author(s): Xin X, Akasaka-Manya K, Manya H, Furukawa J, Kuwahara N, Okada K, Tsumoto H, Higashi N, Kato R, Shinohara Y, Irimura T, Endo T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 9 Pages: 1389-1394
  • DOI: 10.1248/bpb.b15-00415
  • NAID: 130005096979
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 免疫系とバイオマテリアル：総論 (2015)
  • Author(s): 入村達郎、伝田香里
  • Journal Title: Biomaterials Volume: 33(2) Pages: 8-15
  • Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mammary tissue microenvironment determines T cell-dependent breast cancer-associated inflammation. (2015)
  • Author(s): Takahashi K, Nagai N, Ogura K, Tsuneyama K, Saiki I, Irimura T, Hayakawa Y.
  • Journal Title: Cancer Sci Volume: 15
  • NAID: 120006389612
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The macrophage galactose-type lectin can function as an attachment and entry receptor for influenza virus. (2014)
  • Author(s): Ng WC, Liong S, Tate MD, Irimura T, Denda-Nagai K, Brooks AG, Londrigan SL, Reading PC.
  • Journal Title: Jornal of Virology Volume: 88(3) Issue: 3 Pages: 1659-72
  • DOI: 10.1128/jvi.02014-13
  • Peer Reviewed / Open Access
• [Journal Article] Heparanase-mediated cleavage of macromolecular heparin accelerates release of granular components of mast cells from extracellular matrices. (2014)
  • Author(s): Higashi N, Waki M, Sue M, Kogane Y, Shida H, Tsunekawa N, Hasan A, Sato T, Kitahara A, Kasaoka T, Hayakawa Y, Nakajima M, Irimura T.
  • Journal Title: Biochemical Jornal Volume: 458(2) Issue: 2 Pages: 291-9
  • DOI: 10.1042/bj20131463
  • Peer Reviewed
• [Journal Article] Up-regulation of neogenin-1 increases cell proliferation and motility in gastric cancer. (2014)
  • Author(s): Kim SJ, Wang YG, Lee HW, Kang HG, La SH, Choi IJ, Irimura T, Ro JY, Bresalier RS, Chun KH.
  • Journal Title: Oncotarget Volume: 5(10) Pages: 3386-3398
  • Peer Reviewed / Open Access
• [Journal Article] Interaction of Muc4 and ErbB2 in a transgenic mouse model of gallbladder carcinoma: potential pathobiological implications. (2014)
  • Author(s): Miyahara N, Shoda J, Kawamoto T, Ishida H, Ueda T, Akimoto Y, Kawakami H, Irimura T.
  • Journal Title: Oncol Rep Volume: 32(5) Issue: 5 Pages: 1796-1802
  • DOI: 10.3892/or.2014.3443
  • Peer Reviewed
• [Journal Article] Identification of Hirsutine as an anti-metastatic phytochemical by targeting NF-kB activation (2014)
  • Author(s): Chenghua Lou, Kei Takahashi, Tatsuro Irimura, Ikuo Saiki and Yoshihiro Hayakawa
  • Journal Title: International Journal of Oncology Volume: 45 Issue: 5 Pages: 2085-2091
  • DOI: 10.3892/ijo.2014.2624
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages. (2014)
  • Author(s): Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I, Inujima A, Nakayama T, Yoshie O, Sakurai H, Saiki I, Koizumi K.
  • Journal Title: Cancer Sci Volume: 14 Pages: 949-949
  • Peer Reviewed
• [Presentation] 糖鎖付加MUC1を利用したがんワクチンのための基礎的研究：MGLの関与 (2018)
  • Author(s): 伝田香里、入村達郎
  • Organizer: 糖鎖免疫研究会
  • Invited
• [Presentation] ムチンの機能と疾患 (2018)
  • Author(s): 入村達郎
  • Organizer: 御茶ノ水アレルギー研究会
  • Invited
• [Presentation] ムチン２１とその糖鎖：がんによる免疫抑制とアポトーシスの抑制に関わるムチン (2017)
  • Author(s): 入村達郎
  • Organizer: 糖鎖免疫シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2017-01-25
  • Invited
• [Presentation] Comparison on immune response after immunization with glycosylated MUC1 between C57BL/6 mice and MUC1 transgenic mice (2017)
  • Author(s): Denda-Nagai K, Namba A, Noji M, Irimura T
  • Organizer: Mucins in Health and Diseases, 14th Internantional Workshop on Carcinoma-Associated Mucins
  • Int'l Joint Research
• [Presentation] Evaluation of Mucin 1 glycoprotein expression in estrogen receptor-positive primary breast cancer as a predictive marker of neoadjuvant chemotherapy effects and patient outcomes (2017)
  • Author(s): Matsuzawa M, Horimoto Y, Okazaki M, Suzuki M, Fujihira H, Noji M, Denda-Nagai K, Mogushi K, Nakai K, Saito M, Irimura T
  • Organizer: Mucins in Health and Diseases, 14th Internantional Workshop on Carcinoma-Associated Mucins
  • Int'l Joint Research
• [Presentation] Difference in humoral immune response after immunization with glycosylated MUC1 between C57BL/6 mice and MUC1 transgenic mice (2017)
  • Author(s): Kaori Denda-Nagai, Tatsuro Irimura
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Future of glycobiologics (2016)
  • Author(s): Tatsuro Irimura
  • Organizer: Frontier 2016-UT/EPFL Joint Symposium
  • Place of Presentation: Lausanne
  • Year and Date: 2016-12-05
  • Int'l Joint Research / Invited
• [Presentation] MUC1 with truncated O-glycans induces humoral immune responses and suppresses the carcinoma growth and metastasis (2015)
  • Author(s): Kaori Denda-Nagai, Tatsuro Irimura
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-20
  • Int'l Joint Research / Invited
• [Presentation] C-Type Lectins onDendritic Cell and Macrophages Regulate Infection and Immuity (2015)
  • Author(s): Irimura Tatsuro
  • Organizer: LMU-UT Symposium
  • Place of Presentation: Munich, Germany
  • Year and Date: 2015-10-28
  • Int'l Joint Research / Invited
• [Presentation] エボラウイルス-MGL 相互作用の謎 (2015)
  • Author(s): 藤平陽彦、宇佐美克明、伝田香里、古川潤一、篠原康郎、松野啓太、高田礼人、河岡義裕、入村 達郎
  • Organizer: 糖鎖免疫シンポジウム
  • Place of Presentation: 東京医科歯科大学
  • Year and Date: 2015-08-19
  • Int'l Joint Research / Invited
• [Presentation] がん悪性化進展を促す炎症性免疫応答の維持機構におけるIL-17の重要性 (2015)
  • Author(s): 早川芳弘、永井直、斉木育夫、入村達郎
  • Organizer: 第24回日本がん転移学会
  • Place of Presentation: シティプラザ大阪
  • Year and Date: 2015-07-24
  • Invited
• [Presentation] MGL(CD301)in infection and immunity (2015)
  • Author(s): Irimura Tatsuro
  • Organizer: International Workshop on Mucins in Health and diseases
  • Place of Presentation: Cambridge, UK
  • Year and Date: 2015-07-21
  • Int'l Joint Research / Invited
• [Presentation] 薬科学に未来はあるか (2015)
  • Author(s): 入村達郎
  • Organizer: 日本薬剤会第30回記念大会
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2015-05-23
  • Invited
• [Presentation] 糖鎖付加MUC1に対する免疫応答による癌の増殖と転移の制御 (2015)
  • Author(s): 難波愛理、伝田香里、野地美樹、入村達郎
  • Organizer: 第135日本薬学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Heparanase-mediated cleavage of macromolecular heparin accelerates release of granular components of mouse peritoneal cell-derived mast cells. (2014)
  • Author(s): 東伸昭，入村達郎
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] マクロファージガラクトース型C型レクチン（MGL/CD301）による炎症と免疫の制御 (2014)
  • Author(s): 伝田香里、入村達郎
  • Organizer: 第12回糖鎖科学コンソーシアムシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-12-04 – 2014-12-05
  • Invited
• [Presentation] Identification of Hirsutine as an anti-metastatic phytochemical by targeting NF-κB activation. (2014)
  • Author(s): Lou C, Takahashi K, Irimura T, Saiki I, Hayakawa Y.
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] A unique dermal dendritic cell subset that skews the immune response toward Th2. (2014)
  • Author(s): Irimura T.
  • Organizer: MGH and U-Tokyo Joint Symposium on Frontiers in Biomedical Engineering
  • Place of Presentation: Cambridge, MA, USA
  • Year and Date: 2014-09-24 – 2014-09-25
• [Presentation] Public private partnership in Japanese pharmaceutical affairs. (2014)
  • Author(s): Irimura T.
  • Organizer: FIP Congress
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2014-08-31 – 2014-09-04
  • Invited
• [Presentation] マスト細胞顆粒内ヘパリンの切断は細胞外マトリックスからの生理活性物質の放出を促進する (2014)
  • Author(s): 東伸昭，中島元夫、入村達郎
  • Organizer: 第33回日本糖質学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-08-10 – 2014-08-12
• [Presentation] Vd1T細胞を起点とする自然炎症はがん悪性化を促進する (2014)
  • Author(s): 早川芳弘、済木育夫、入村達郎
  • Organizer: 第23回がん転移学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] Requirement of CD4T cells for establishing inflammatory tumor microenvironment in 4T1breast cancer model. (2014)
  • Author(s): Takahashi K, Nagai N, Saiki I, Irimura T, Hayakawa Y.
  • Organizer: The 22nd International Symposium on Molecular Cell Biology of Macrophages.
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2014-06-02 – 2014-06-03
• [Book] 感染と免疫 第４版 (2017)
  • Author(s): J．Playfair、G．Bancroft、入村 達郎、伝田 香里、加藤 健太郎、佐藤 佳代子、築地 信
  • Total Pages: 264
  • Publisher: 東京化学同人
  • ISBN: 9784807908974
• [Book] C-Type Lectin Receptors in Immunity (2016)
  • Author(s): Kaori Denda-Nagai and Tatsuro Irimura
  • Publisher: Springer