Secretome analysis of tumor stroma involved in the process of cancer progression

• Project/Area Number: 18K07244
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Umezu Tomohiro 東京医科大学, 医学部, 准教授 (40385547)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: がん間質 / がん微小環境 / 多発性骨髄腫 / miRNA / エクソソーム / セクレトーム / セクレトーム解析 / MGUS

Outline of Final Research Achievements

In this study, we investigated the role of extracellular vesicles (EVs) from BMSCs derived from MM patients (MM-BMSCs). EV-encapsulated miR-10a expression was high while intracellular miR-10a was low in MM-BMSCs. We therefore hypothesized that miR-10a was packaged into EVs that were actively released into the extracellular space. Inhibition of EV release resulted in accumulation of intracellular miR-10a, inhibition of cell proliferation, and induction of apoptosis in MM-BMSCs. In contrast, proliferation and apoptosis of BMSCs derived from healthy individuals were unaffected by inhibition of EV release. Furthermore, miR-10a derived from MM-BMSCs was transferred into MM cells via EVs and enhanced their proliferation. These results suggest that inhibition of EV release induced apoptosis in MM-BMSCs and inhibited MM cell growth, indicating a possible role for MM-BMSC-targeted therapy.

Academic Significance and Societal Importance of the Research Achievements

本研究では機能的、すなわち腫瘍細胞の進展をサポート可能な間質細胞が放出する因子を探索した。そして、がん間質細胞を標的とする治療法の意義として、上皮性のがん細胞ががん間質細胞へと形質転換（Epithelial-mesenchymal transition: EMT）し、高い転移能やアポトーシスに対する抵抗性を獲得してしまうことが知られており、抗がん剤によって腫瘍細胞を抑制できたとしても、がん間質細胞が残存していると再発や治療抵抗性に多大な影響を及ぼすことが予想され、腫瘍細胞とともにがん間質細胞の撲滅が有効的であると考えられる。

Research Products

• [Journal Article] Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing (2021)
  • Author(s): Asakage M, Usui Y, Nezu N, Shimizu H, Tsubota K, Umazume K, Yamakawa N, Umezu T, Suwanai H, Kuroda M, Goto H.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: in press Issue: 11 Pages: 3548-3548
  • DOI: 10.3390/jcm9113458
  • NAID: 120007183860
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of liver and blood miRNA in precancerous conditions (2020)
  • Author(s): Umezu Tomohiro、Tsuneyama Koichi、Kanekura Kohsuke、Hayakawa Michiyo、Tanahashi Toshihito、Kawano Mitsuoki、Taguchi Y-h、Toyoda Hidenori、Tamori Akihiro、Kuroda Masahiko、Murakami Yoshiki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 21766-21766
  • DOI: 10.1038/s41598-020-78500-1
  • Peer Reviewed / Open Access
• [Journal Article] Effect of the extracellular componebt of bone marrow mesenchymal stromal cells from healthy donors on hematologic neoplasms and their angiogenesis. (2020)
  • Author(s): Gladkov N, Umezu T, Imanishi S, Kawana C, Ohyashiki JH, Ohyashiki K.
  • Journal Title: Hum Cell. Volume: 33(3) Issue: 3 Pages: 599-609
  • DOI: 10.1007/s13577-020-00332-y
  • Peer Reviewed
• [Journal Article] Downregulation of extracellular vesicle microRNA-101 derived from bone marrow mesenchymal stromal cells in myelodysplastic syndrome with disease progression. (2020)
  • Author(s): Saitoh Y, Umezu T, Imanishi S, Asano M, Yoshizawa S, Katagiri S, Suguro T, Fujimoto H, Akahane D, Kobayashi-Kawana C, Ohyashiki JH, Ohyashiki K.
  • Journal Title: Oncol Lett. Volume: 19(3) Pages: 2053-2061
  • DOI: 10.3892/ol.2020.11282
  • Peer Reviewed / Open Access
• [Journal Article] Predisposed genomic instability in pre-treatment bone marrow evolves to therapy-related myeloid neoplasms in malignant lymphoma. (2019)
  • Author(s): Katagiri S, Makishima H, Azuma K, Nannya Y, Saitoh Y, Yoshizawa S, Akahane D, Fujimoto H, Ito Y, Velaga R, Umezu T, Ohyashiki JH, Ogawa S, Ohyashiki K.
  • Journal Title: Haematologica. Volume: Nov 7 Issue: 7 Pages: 229856-229856
  • DOI: 10.3324/haematol.2019.229856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of multiple myeloma bone marrow stromal cell apoptosis by inhibiting extracellular vesicle miR-10a secretion. (2019)
  • Author(s): Umezu T, Imanishi S, Yoshizawa S, Kawana C, Ohyashiki JH, Ohyashiki K.
  • Journal Title: Blood Advances Volume: 3(21) Issue: 21 Pages: 3228-3240
  • DOI: 10.1182/bloodadvances.2019000403
  • Peer Reviewed / Open Access
• [Journal Article] A novel non-invasive monitoring assay of 5-azacitidine efficacy using global DNA methylation of peripheral blood in myelodysplastic syndrome. (2019)
  • Author(s): Asano M, Ohyashiki JH, Kobayashi-Kawana C, Umezu T, Imanishi S, Azuma K, Akahane D, Fujimoto H, Ito Y, Ohyashiki K.
  • Journal Title: Drug Des Devel Ther. Volume: 13 Pages: 1821-1833
  • DOI: 10.2147/dddt.s195071
  • Peer Reviewed / Open Access
• [Journal Article] Lineage-specific RUNX2 super-enhancer activates MYC via a chromosomal translocation and promotes the development of blastic plasmacytoid dendritic cell neoplasm (2019)
  • Author(s): Kubota S, Tokunaga K, Umezu T, Yokomizo-Nakano T, Oshima M, Tan KT, Yang H, Kanai A. Iwanaga E, Asou N, Maeda T, Nakagata N. Ito T, Iwama A. Ohyashiki K, Osato M, Sashida G.
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 1653-1653
  • DOI: 10.1038/s41467-019-09710-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BIM deletion polymorphism accounts for lack of favorable outcome in Japanese females with follicular lymphoma. (2019)
  • Author(s): Ito Y, Umezu T, Tadokoro K, Saito Y, Katagiri S, Suguro T, Asano M, Yoshizawa S, Akahane D, Tanaka Y, Fujimoto H, Okabe S, Gotoh M, Tauchi T, Kawana C, Ohyashiki JH, Nakamura N, Ohyashiki K.
  • Journal Title: Leuk Lymphoma. Volume: 60(5) Issue: 5 Pages: 1283-1288
  • DOI: 10.1080/10428194.2018.1529310
  • Peer Reviewed / Open Access
• [Journal Article] Maintenance 5-azacytidine therapy by MRD monitoring after allogeneic HSCT in myeloid/lymphoid neoplasms with FGFR1 rearrangement. (2019)
  • Author(s): Katagiri S, Umezu T, Azuma K, Kobayashi C, Akahane D, Suguro T, Furuya N, Fujimoto H, Nakamura N, Ohyashiki JH, Ohyashiki K.
  • Journal Title: Bone Marrow Transplant. Volume: - Issue: 7 Pages: 1148-1150
  • DOI: 10.1038/s41409-019-0436-1
  • Peer Reviewed
• [Journal Article] Exosomal miRNA Signatures for Late-Onset Acute Graft-Versus-Host Disease in Allogenic Hematopoietic Stem Cell Transplantation. (2018)
  • Author(s): Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K.
  • Journal Title: Int J Mol Sci. Volume: 19(9) Issue: 9 Pages: 2493-2493
  • DOI: 10.3390/ijms19092493
  • Peer Reviewed / Open Access
• [Journal Article] Chromatin Regulation by HP1γ Contributes to Survival of 5-Azacytidine-Resistant Cells. (2018)
  • Author(s): Imanishi S, Umezu T, Kobayashi C, Ohta T, Ohyashiki K, Ohyashiki JH.
  • Journal Title: Front Pharmacol. Volume: 9 Pages: 1166-1166
  • DOI: 10.3389/fphar.2018.01166
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicle (EV)- mediated cell-cell communication in hematologic neoplasms (2018)
  • Author(s): Ohyashiki JH, Umezu T, Ohyashiki K
  • Journal Title: Philosophical Transactions of the Royal Society B: Biological Sciences Volume: 373 Issue: 1737 Pages: 1737-1737
  • DOI: 10.1098/rstb.2016.0484
  • Peer Reviewed
• [Journal Article] Stratification of mouse vaginal epithelium. 1. Development of three-dimensional models in vitro with clonal cell lines (2018)
  • Author(s): Ogawa-Tominaga M, Umezu T, Nakajima T, Tomooka Y.
  • Journal Title: Biology of Reproduction Volume: 99(4) Pages: 715-726
  • DOI: 10.1093/biolre/ioy114
  • Peer Reviewed
• [Journal Article] Stratification of mouse vaginal epithelium 2. Identification of factors inducing stratification (2018)
  • Author(s): Takashina R, Nakajima T, Umezu T, Murakami Y, Tomooka Y.
  • Journal Title: Biology of Reproduction Volume: 99(4) Issue: 4 Pages: 727-734
  • DOI: 10.1093/biolre/ioy113
  • Peer Reviewed
• [Journal Article] Hidden FLT3-D835Y clone in FLT3-ITD-positive acute myeloid leukemia that evolved into very late relapse with T-lymphoblastic leukemia (2017)
  • Author(s): Katagiri S, Umezu T, Asano M, Akahane D, Azuma K, Makishima H, Yoshida K, Watatani Y, Chiba K, Miyano S, Ogawa S, Ohyashiki JH, Ohyashiki K
  • Journal Title: Leukemia and Lymphoma Volume: 3 Issue: 6 Pages: 1-4
  • DOI: 10.1080/10428194.2017.1382696
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Acerola derived exosome-like nanovesicles enhances the repair of ultraviolet B-induced DNA damage in cultured skin fibroblasts (2020)
  • Author(s): Tomohiro Umezu, Kazuma Ohyashiki, Masahiko Kuroda.
  • Organizer: ANNUAL MEETING ISEV2020
  • Int'l Joint Research
• [Presentation] アセロラ果汁由来小胞を用いたドラッグデリバリーシステムの開発 (2020)
  • Author(s): 梅津知宏、高梨正勝、大野慎一郎、村上善基、黒田雅彦
  • Organizer: 第7回日本細胞外小胞学会
• [Presentation] Aging-associated aberrant microRNA expression plays a role in hepatocarcinogenesis (2020)
  • Author(s): Tomohiro Umezu, Akihiro Tamori, Takahiro Ochiya, Masahiko Kuroda, Yoshiki Murakami
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Extravellular vesicles derived from bone marrow stromal cells promote evasion of multiple myeloma cells from NK cell anti-tumor activity (2019)
  • Author(s): Tomohiro Umezu, Kazuma Ohyashiki, Masahiko Kuroda.
  • Organizer: ANNUAL MEETING ISEV 2019
  • Int'l Joint Research
• [Presentation] がん間質細胞由来エクソソームはNK細胞の抗腫瘍効果を抑制する (2019)
  • Author(s): 梅津 知宏、大屋敷一馬、黒田雅彦．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 肺がん患者由来エクソソームmiRNAを用いた診断バイオマーカーの探索 (2019)
  • Author(s): 梅津 知宏、高梨 正勝、斎藤 彰、工藤 勇人、嶋田 善久、大平 達夫、池田 徳彦、黒田 雅彦
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] アセロラ果汁由来小胞の機能解析とその有用性に関する研究 (2019)
  • Author(s): 梅津 知宏、高梨正勝、大野慎一郎、黒田雅彦
  • Organizer: 第6回日本細胞外小胞学会学術集会
• [Presentation] ステロイド抵抗性急性GVHDに対するヒト骨髄由来間葉系幹細胞治療 (2018)
  • Author(s): 片桐誠一朗、吉澤成一郎、梅津知宏、齋藤優、勝呂多光子、赤羽大悟、田中裕子、古屋奈穂子、藤本博昭、後藤守孝、大屋敷一馬
  • Organizer: 免疫アレルギー研究会
• [Presentation] Characterization of novel bona marrow stromal cells from healthy donors. (2018)
  • Author(s): Umezu T, Gladkova N, Imanishi S, Ohyashiki K, Ohyashiki JH
  • Organizer: 第36回ヒト細胞学会学術集会
• [Presentation] Extracellular vesicle-mediated miRNA transfer enhances growth and survival of multiple myeloma. (2018)
  • Author(s): Umezu T, Imanishi S, Yoshizawa S, Ohyashiki K, Ohyashiki JH
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 5-azacytidine targets chromatin regulation through piRNA pathway. (2018)
  • Author(s): Imanishi S, Azuma K, Umezu T, Kawana C, Ohyashiki K, Ohyashiki JH
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Lineage-specific RUNX2uper-enhncer activates MYC via a chromosomal translocation and promotes the BPDCN. (2018)
  • Author(s): Kubota S, Umezu T, Iwama A, Ohyashiki K, Osato M, Sashida G
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] The role of extracellular vesicle-mediated miR-10a transfer in bone marrow microenvironment of patients with multiple myeloma. (2018)
  • Author(s): Umezu T, Ohyashiki K, Ohyashiki JH
  • Organizer: International Society for Extracellular Vesicles 2018
  • Int'l Joint Research
• [Presentation] Bone marrow mesenchymal stromal cells from healthy donors secrete anti-angiogenic EVs as well as soluble factors having growth inhibitory effect in MM. (2018)
  • Author(s): Umezu T, Imanishi S, Gladkova N, Ohyashiki K, Ohyashiki JH
  • Organizer: European Hematology Association 2018
  • Int'l Joint Research