Extracellular Hsp90 plays a pivotal role in innate immunity and adaptive immunity

• Project/Area Number: 24659165
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: SATO Noriyuki 札幌医科大学, 医学部, 教授 (50158937)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 熱ショック蛋白質 / 無菌性炎症 / 自然免疫 / 獲得免疫 / 樹状細胞 / クロスプレゼンテーション / 酸化酵素 / Hsp90 / ERO1 / 慢性炎症 / Hsp90レセプター / 酸化ストレス / HSP90 / ERO1-α / HSP90レセプター / エンドサイトーシス / 初期エンドソーム / レセプター

Outline of Final Research Achievements

Extracellular heat shock proteins (HSPs) have been shown to initiate an aseptic inflammation via an activation of antigen presenting cells including dendritic cells. Moreover, we have shown that extracellular Hsp90-antigen complex is efficiently cross-presented by dendritic cells and stimulates antigen-specific T cells. Thus, extracellular Hsp90 plays a crucial role in the activation of innate immunity and adaptive immunity. In this study, we have identified ER-resident oxidase ERO1-α as a candidate of Hsp90 receptor. The cell surface expression as well as ER expression of ERO1-α was augmented when dendritic cells were exposed to hypoxia and oxidative stress caused by H2O2 treatment. Extracellular Hsp90 bound to ERO1-α expressed on the cell surface of dendritic cells. We are currently investigating whether ERO1-α-bound Hsp90 is endocytosed and activates dendritic cells. These results will explain how endogenous extracellular HSPs impact on the inflammation and immunity.

Research Products

• [Journal Article] Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells (2015)
  • Author(s): Tsutomu Tanaka, Koichi Okuya, Goro Kutomi, Akari Takaya, Toshimitsu Kajiwara, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Koichi Hirata, Yoshiharu Okamoto, Noriyuki Sato, Yasuaki Tamura
  • Journal Title: Cancer Science Volume: 106 Issue: 1 Pages: 18-24
  • DOI: 10.1111/cas.12570
  • NAID: 120005593448
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer-associated oxidoreductase ERO1-α drives the production of tumor-promoting myeloid-derived suppressor cells via oxidative protein folding. (2015)
  • Author(s): Tsutomu Tanaka, Toshimitsu Kajiwara, Toshihiko Torigoe, Yoshiharu Okamoto, Noriyuki Sato, Yasuaki Tamura
  • Journal Title: J Immunology Volume: 194 Issue: 4 Pages: 2004-2010
  • DOI: 10.4049/jimmunol.1402538
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of hepatocyte growth factor in prostate cancer may indicate a biochemical recurrence after radical prostatectomy. (2015)
  • Author(s): Nishida S, Hirohashi Y, Torigoe T, Nojima M, Inoue R, Kitamura H, Tanaka T, Asanuma H, Sato N, Masumori N.
  • Journal Title: Anticancer Res Volume: 35 Pages: 413-418
  • Peer Reviewed
• [Journal Article] PolyI:C and mouse survivin artificially embedding human 2B peptide induce a CD4+ T cell response to autologous survivin in HLA-A*2402 transgenic mice. (2015)
  • Author(s): Kasamatsu J, Takahashi S, Azuma M, Matsumoto M, Morii-Sakai A, Imamura M, Teshima T, Takahashi A, Hirohashi Y, Torigoe T, Sato N, Seya T.
  • Journal Title: Immunobiology Volume: 220 Issue: 1 Pages: 74-82
  • DOI: 10.1016/j.imbio.2014.08.017
  • Peer Reviewed
• [Journal Article] Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity. (2014)
  • Author(s): Yasuda K, Torigoe T, Mariya T, Asano T, Kuroda T, Matsuzaki J, Ikeda K, Yamauchi M, Emori M, Asanuma H, Hasegawa T, Saito T, Hirohashi Y, Sato N.
  • Journal Title: Lab Invest Volume: 94 Issue: 12 Pages: 1355-69
  • DOI: 10.1038/labinvest.2014.122
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Specific targeting of a naturally presented osteosarcoma antigen, papillomavirus binding factor peptide, using an artificial monoclonal antibody. (2014)
  • Author(s): Tsukahara T, Emori M, Murata K, Hirano T, Muroi N, Kyono M, Toji S, Watanabe K, Torigoe T, Kochin V, Asanuma H, Matsumiya H, Yamashita K, Himi T, Ichimiya S, Wada T, Yamashita T, Hasegawa T, Sato N.
  • Journal Title: J Biol Chem Volume: 289 Issue: 32 Pages: 22035-22047
  • DOI: 10.1074/jbc.m114.568725
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypoxia-inducible factor (HIF)-independent expression mechanism and novel function of HIF prolyl hydroxylase-3 in renal cell carcinoma. (2014)
  • Author(s): Tanaka T, Torigoe T, Hirohashi Y, Sato E, Honma I, Kitamura H, Masumori N, Tsukamoto T, Sato N.
  • Journal Title: J Cancer Res Clin Oncol Volume: 140 Issue: 3 Pages: 503-513
  • DOI: 10.1007/s00432-014-1593-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heat shock protein DNAJB8 is a novel target for immunotherapy of colon cancer-initiating cells. (2014)
  • Author(s): Morita R, Nishizawa S, Torigoe T, Takahashi A, Tamura Y, Tsukahara T, Kanaseki T, Sokolovskaya A, Kochin V, Kondo T, Hashino S, Asaka M, Hara I, Hirohashi Y, Sato N.
  • Journal Title: Cancer Sci Volume: 105 Issue: 4 Pages: 389-395
  • DOI: 10.1111/cas.12362
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Production of multiple CTL epitopes from multiple tumor-associated antigens. (2014)
  • Author(s): Morita R, Hirohashi Y, Nakatsugawa M, Kanaseki T, Torigoe T, Sato N.
  • Journal Title: Methods Mol Biol Volume: 1139 Pages: 345-55
  • DOI: 10.1007/978-1-4939-0345-0_28
  • ISBN: 9781493903443, 9781493903450
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer. (2014)
  • Author(s): Mariya T, Hirohashi Y, Torigoe T, Asano T, Kuroda T, Yasuda K, Mizuuchi M, Sonoda T, Saito T, Sato N.
  • Journal Title: Cancer Immunol Res Volume: 2 Issue: 12 Pages: 1220-9
  • DOI: 10.1158/2326-6066.cir-14-0101
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ERAAP and tapasin independently edit the amino and carboxyl termini of MHC class I peptides. (2013)
  • Author(s): Kanaseki T, Lind KC, Escobar H, Nagarajan N, Reyes-Vargas E, Rudd B, Rockwood AL, Van Kaer L, Sato N, Delgado JC, Shastri N.
  • Journal Title: J Immunol. Volume: Aug 15;191(4) Issue: 4 Pages: 1547-55
  • DOI: 10.4049/jimmunol.1301043
  • Peer Reviewed
• [Journal Article] High Expression of CD109 Antigen Regulates the Phenotype of Caneer Stem-Like Cells/Cancer-lnitiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma. (2013)
  • Author(s): Emori M, Tsukahara T, Murase M, Kano M, Murata K, Takahashi A, Kubo T, Asanuma H, Yasuda K, Kochin V, Kaya M, Nagoya S, Nishio J, Iwasaki H, Sonoda T, Hasegawa T, Torigoe T, Wada T, Yamashita T, Sato N.
  • Journal Title: PLoS One. Volume: 8 Issue: 12 Pages: e84187-e84187
  • DOI: 10.1371/journal.pone.0084187
  • Peer Reviewed
• [Journal Article] Potential survival benefit of anti-apoptosis protein, survivin-derived peptide vaccine with and without interferon alpha therapy for patients with advanced or recurrent urothelial cancer: results from phase I clinical trials (2013)
  • Author(s): Tanaka T, Kitamura H, Inoue R, Nishida S, Takahashi-Takaya A, Kawami S, Torigoe S, Hirohashi Y, Tsukamoto T, Sato N, Masumori N
  • Journal Title: Clin Dev Immunol Volume: 2013 Pages: 262967-262967
  • DOI: 10.1155/2013/262967
  • Peer Reviewed
• [Journal Article] Ectopically expressed variant form of sperm mitochondria-associated cysteine-rich protein augments tumorigenicity of the stem cell population of lung adenocarcinoma cells. (2013)
  • Author(s): Takahashi A, Hirohashi Y, Torigoe T, Tamura Y, Tsukahara T, Kanaseki T, Kochin V, Saijo H, Kubo T, Nakatsugawa M, Asanuma H, Hasegawa T, Kondo T, Sato N.
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: e69095-e69095
  • DOI: 10.1371/journal.pone.0069095
  • Peer Reviewed
• [Journal Article] Ovarian cancer stem cells are enriched in side population and aldehyde dehydrogenase bright overlapping population. (2013)
  • Author(s): Yasuda K, Torigoe T, Morita R, Kuroda T, Takahashi A, Matsuzaki J, Kochin V, Asanuma H, Hasegawa T, Saito T, Hirohashi Y, Sato N.
  • Journal Title: PLoS One Volume: 8(8) Issue: 8 Pages: e68187-e68187
  • DOI: 10.1371/journal.pone.0068187
  • Peer Reviewed
• [Journal Article] Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells (2013)
  • Author(s): Matsuzaki J, Torigoe T, Hirohashi Y, Tamura Y, Asanuma H, Nakazawa E, Saka E, Yasuda K, Takahashi S, Sato N
  • Journal Title: Pathol Int. Volume: 63(8) Issue: 8 Pages: 391-7
  • DOI: 10.1111/pin.12079
  • Peer Reviewed
• [Journal Article] Small proline-rich protein-1B is overexpressed in human oral squamous cell cancer stem-like cells and is related to their growth through activation of MAP kinase signal. (2013)
  • Author(s): Michifuri Y, Hirohashi Y, Torigoe T, Miyazaki A, Fujino J, Tamura Y, Tsukahara T, Kanaseki T, Kobayashi J, Sasaki T, Takahashi A, Nakamori K, Yamaguchi A, Hiratsuka H, Sato N.
  • Journal Title: Biochem Biophys Res Commun Volume: 439 Issue: 1 Pages: 96-102
  • DOI: 10.1016/j.bbrc.2013.08.021
  • Peer Reviewed
• [Journal Article] Six-transmembrane epithelial antigen of the prostate-1 plays a role for in vivo tumor growth via intercellular communication (2013)
  • Author(s): Yamamoto T, Tamura Y, Kobayashi J, Kamiguchi K, Hirohashi Y, Miyazaki A, Torigoe T, Asanuma H, Hiratsuka H, Sato N
  • Journal Title: Exp. Cell Res. Volume: 319 Issue: 17 Pages: 2617-29
  • DOI: 10.1016/j.yexcr.2013.07.025
  • Peer Reviewed
• [Journal Article] AIDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and AIDH1 high expression is associated with poor prognosis. (2013)
  • Author(s): Kuroda T, Hirohashi Y, Torigoe T, Yasuda K, Takahashi A, Asanuma H, Morita R, Mariya T, Asano T, Mizuuchi M, Saito T, Sato N.
  • Journal Title: PLoS One Volume: 8(6) Issue: 6 Pages: e65158-e65158
  • DOI: 10.1371/journal.pone.0065158
  • Peer Reviewed
• [Journal Article] Human Endoplasmic Reticulum Oxidoreductin 1-α(hERO1-α) is a Novel Predictor for Poor Prognosis of Breast Cancer (2013)
  • Author(s): Kutomi G, Tamura Y, Tanaka T, Kajiwara T, Kukita K, Ohmura T, Shima H, Takamaru T, Satomi F, Suzuki Y, Torigoe T, Sato N, Hirata H
  • Journal Title: Cancer Sci. Volume: 104 Issue: 8 Pages: 1091-6
  • DOI: 10.1111/cas.12177
  • Peer Reviewed
• [Journal Article] Constitutive expression and activation of stress response genes in cancer stem-like cells/tumour initiating cells: Potent targets for cancer stem cell therapy. (2013)
  • Author(s): Torigoe T, Hirohashi Y, Yasuda K, Sato N.
  • Journal Title: Int J Hyperthermia. Volume: 29(5) Pages: 436-41
  • Peer Reviewed
• [Journal Article] Resveratrol inhibits fibrogenesis and induces apoptosis in keloid fibroblasts. (2013)
  • Author(s): Ikeda K, Torigoe T, Matsumoto Y, Fujita T, Sato N, Yotsuyanagi T.
  • Journal Title: Wound Repair Regen. Volume: 21(4) Issue: 4 Pages: 616-23
  • DOI: 10.1111/wrr.12062
  • Peer Reviewed
• [Journal Article] Preferential expression of cancer/testis genes in cancer stem-like cells : proposal of a novel sub-category, cancer/testis/stem gene. (2013)
  • Author(s): Yamada R, Takahashi A, Torigoe T, Morita R, Tamura Y, Tsukahara T, Kanaseki T, Kubo T, Watarai K, Kondo T, Hirohashi Y, Sato N.
  • Journal Title: Tissue Antigens. Volume: 81(6) Issue: 6 Pages: 428-34
  • DOI: 10.1111/tan.12113
  • Peer Reviewed
• [Journal Article] Prostate cancer stem-like cells/cancer-initiating cells have an autocrine system of hepatocyte growth factor. (2013)
  • Author(s): Nishida S, Hirohashi Y, Torigoe T, Inoue R, Kitamura H, Tanaka T, Takahashi A, Asanuma H, Masumori N, Tsukamoto T, Sato N.
  • Journal Title: Cancer Sci Volume: 104 Issue: 4 Pages: 431-6
  • DOI: 10.1111/cas.12104
  • Peer Reviewed
• [Journal Article] Immunotherapeutic benefit ofα-interferon (IFNα) in survivin2B-derived peptide vaccination for advanced pancreatic cancer patients (2013)
  • Author(s): Kameshima H, Tsuruma T, Kutomi G, Shima H, Iwayama Y, Kimura Y, Imamura M, Torigoe T, Takahashi A, Hirohashi Y, Tamura Y, Tsukahara T, Kanaseki T, Sato N, Hirata K
  • Journal Title: Cancer Sci. Volume: 104 Issue: 1 Pages: 124-129
  • DOI: 10.1111/cas.12046
  • Peer Reviewed
• [Journal Article] Nuclear, but not cytoplasmic, localization of survivin as a negative prognostic factor for survival in upper urinary tract urothelial carcinoma (2013)
  • Author(s): Kitamura H, Torigoe T, Hirohashi Y, Asanuma H, Inoue R, Nishida S, Tanaka T, Masumori N, Sato N, Tsukamoto T
  • Journal Title: Virchows Arch Volume: 462 Issue: 1 Pages: 101-107
  • DOI: 10.1007/s00428-012-1343-7
  • Peer Reviewed
• [Journal Article] Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract. (2013)
  • Author(s): Kitamura H, Torigoe T, Hirohashi Y, Asanuma H, Inoue R, Nishida S, Tanaka T, Fukuta F, Masumori N, Sato N, Tsukamoto T.
  • Journal Title: Mod Pathol. Volume: 26(1) Issue: 1 Pages: 117-24
  • DOI: 10.1038/modpathol.2012.139
  • Peer Reviewed
• [Journal Article] Expression and function of FERMT genes in colon carcinoma cells. (2013)
  • Author(s): Kiriyama K, Hirohashi Y, Torigoe T, Kubo T, Tamura Y, Kanaseki T, Takahashi A, Nakazawa E, Saka E, Ragnarsson C, Nakatsugawa M, Inoda S, Asanuma H, Takasu H, Hasegawa T, Yasoshima T, Hirata K, Sato N.
  • Journal Title: Anticancer Res. Volume: 33(1) Pages: 167-73
  • Peer Reviewed
• [Journal Article] DNA methyltransferase 1 is essential for initiation of the colon cancers (2013)
  • Author(s): Morita R,Hirohashi Y,Suzuki H, et al
  • Journal Title: Experimental and Molecular Pathology Volume: 94 Issue: 2 Pages: 322-329
  • DOI: 10.1016/j.yexmp.2012.10.004
  • Peer Reviewed
• [Journal Article] Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. (2012)
  • Author(s): Tamura Y, Torigoe T, Kukita K, Saito K, Okuya K, Kutomi G, Hirata K, Sato N.
  • Journal Title: Immunotherapy Volume: 8 Issue: 8 Pages: 841-852
  • DOI: 10.2217/imt.12.75
  • Peer Reviewed
• [Journal Article] New paradigm for intrinsic function of heat shock proteins as endogenous ligands in inflammation and innate immunity. (2012)
  • Author(s): Tamura Y, Torigoe T, Kutomi G, Hirata K, Sato N.
  • Journal Title: Curr Mol Med. Volume: 121 Pages: 1198-1206
  • Peer Reviewed
• [Journal Article] Heat shock enhances the expression of cytotoxic granule proteins and augments the activities of tumor-associated antigen-specific cytotoxic T lymphocytes (2012)
  • Author(s): Takahashi A, Torigoe T, Tamura Y, Kanaseki T, Tsukahara T, Sasaki Y, Kameshima H, Tsuruma T, Hirata K, Tokino T, Hirohashi Y, Sato N
  • Journal Title: Cell Stress Chaperones Volume: 17 Issue: 6 Pages: 757-763
  • DOI: 10.1007/s12192-012-0348-0
  • Peer Reviewed
• [Journal Article] Heat shock protein 40 family, DNAJB8 is expressed in renal cancer stem-like cell, controls the tumor-initiating ability and can be a potent target of immunotherapy. (2012)
  • Author(s): Nishizawa, S., Mori, T., Hirohashi, Y., Torigoe, T., Tamura, Y., Kamiguchi, K., Takahashi, A., Kanaseki, T., Nakazawa, E., Asanuma, H., Sokolovskaya, A., Morita, R., Yamada, R., Fujii, R., Kondo, T., Hasegawa, T., Hara, I. and Sato, N.
  • Journal Title: Cancer Res Volume: (in press) Issue: 11 Pages: 2844-54
  • DOI: 10.1158/0008-5472.can-11-3062
  • Peer Reviewed
• [Presentation] ヒトがん幹細胞の免疫制御 (2014)
  • Author(s): 佐藤 昇志
  • Organizer: 第26回日本胆肝膵外科学会・学術集会
  • Place of Presentation: 和歌山県民文化会館（和歌山県和歌山市）
  • Year and Date: 2014-06-12
  • Invited
• [Presentation] HSPs link the innate immunity and adaptive immunity (2012)
  • Author(s): 田村 保明、鳥越 俊彦、佐藤 昇志
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌市
  • Invited
• [Presentation] がん免疫治療・予防 ―がん幹細胞の免疫制御を介して-
  • Author(s): 佐藤昇志
  • Organizer: 第45回和歌山県医師会医学会総会特別講演
  • Place of Presentation: 和歌山
  • Invited
• [Presentation] 癌免疫
  • Author(s): 佐藤昇志
  • Organizer: 第45回日本小児感染症学会総会・学術集会特別講演
  • Place of Presentation: 札幌
  • Invited
• [Presentation] Human cancer stem cells and natural antigenic peptides
  • Author(s): 佐藤昇志
  • Organizer: 第72回日本癌学会学術総会シンポジウム
  • Place of Presentation: 横浜
  • Invited
• [Presentation] Immunobiological linkage of human cancer stem cell/cancer-initiating cell with cellular stress response
  • Author(s): 佐藤昇志
  • Organizer: 第86回日本生化学会大会シンポジウム
  • Place of Presentation: 横浜
  • Invited
• [Book] 腫瘍．器官病理学 (2013)
  • Author(s): 佐藤昇志、笠原正典編著
  • Total Pages: 1018
  • Publisher: 南山堂
• [Remarks] 札幌医科大学病理学第1講座
  • URL: http://web.sapmed.ac.jp/patho1/
• [Patent(Industrial Property Rights)] 腫瘍抗原ペプチド (2014)
  • Inventor(s): 宮本昇、佐藤昇志、他
  • Industrial Property Rights Holder: 宮本昇、佐藤昇志、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-09
• [Patent(Industrial Property Rights)] FAM83B由来腫瘍抗原ペプチド (2014)
  • Inventor(s): 高谷あかり、佐藤昇志、他
  • Industrial Property Rights Holder: 高谷あかり、佐藤昇志、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-03
  • Overseas
• [Patent(Industrial Property Rights)] BORIS由来腫瘍抗原ペプ チド (2014)
  • Inventor(s): 浅野拓也、佐藤昇志、他
  • Industrial Property Rights Holder: 浅野拓也、佐藤昇志、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-09-24
• [Patent(Industrial Property Rights)] 腫瘍抗原ペプチド (2014)
  • Inventor(s): 増田圭基、佐藤昇志、他
  • Industrial Property Rights Holder: 増田圭基、佐藤昇志、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-07-11
  • Overseas