Elucidation of molecular mechanisms of chemotherapy resistance based on interactions between tumor cells and tumor microenvironment

• Project/Area Number: 17H05043
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Veterinary medical science
• Research Institution: The University of Tokyo
• Principal Investigator: Tomiyasu Hirotaka 東京大学, 大学院農学生命科学研究科(農学部), 助教 (70776111)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥24,440,000 (Direct Cost: ¥18,800,000、Indirect Cost: ¥5,640,000); Fiscal Year 2019: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2017: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
• Keywords: エクソソーム / 化学療法耐性 / miRNA / 腫瘍微小環境 / 腫瘍免疫

Outline of Final Research Achievements

In this study, I focused on the interactions between tumor cells and immune cells via extracellular vesicles, exosomes, and investigated the molecular mechanisms involved in chemotherapy resistance in tumors.First, the molecular profiles of exosomes derived from canine lymphoma cells were comprehensively analyzed, and I identified the nucleic acids and proteins whose amounts within exosomes were different between chemotherapy agent-sensitive and resistant cells. In addition, it was suggested that CD82 protein has the functions to suppress the progression of tumors. Furthermore, it was revealed that tumor cell-derived exosomes significantly changed the expression levels of inflammatory cytokines in monocytes and lymphocytes and cell death was induced in cytotoxic T cells.
I believe that these results provided novel insights that contribute to the elucidation of the molecular pathology of neoplastic diseases.

Academic Significance and Societal Importance of the Research Achievements

悪性腫瘍に対する化学療法において抗がん剤に対する耐性獲得は治療に限界をもたらす主たる要因となっているが、未だその分子機構の解明やその克服には至っていない。これまでの当該分野の研究では主に腫瘍細胞自身に起こる変化に着目してきたが、本研究では腫瘍細胞と周囲の微小環境、特に免疫細胞との相互作用という全く新たな着眼点からその分子病態を解析したものである。本研究から得られた成果は腫瘍性疾患の分子病態に関する新たな知見を提供するものであり、獣医学領域のみならず人医学領域における研究にも貢献するものと考えている。

Research Products

• [Int'l Joint Research] National Taiwan University(その他の国・地域(台湾))
• [Int'l Joint Research] National Taiwan University(その他の国・地域（台湾）)
• [Int'l Joint Research] University of California, Davis(米国)
• [Journal Article] Comparison of the efficacy of cyclosporine and leflunomide in treating inflammatory colorectal polyps in miniature dachshunds (2020)
  • Author(s): Tani A、Seno T、Yokoyama N、Nakagawa T、Tomiyasu H、Goto-Koshino Y、Tsujimoto H、Ohno K
  • Journal Title: Journal of Veterinary Medical Science Volume: 82 Issue: 4 Pages: 437-440
  • DOI: 10.1292/jvms.19-0560
  • NAID: 130007829876
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Imatinib enhances the anti-tumour effect of doxorubicin in canine B-cell lymphoma cell line (2019)
  • Author(s): Chen W、Liu I、Tomiyasu H、Lee J、Cheng C、Liao AT、Liu B、Liu C、Lin C
  • Journal Title: The Veterinary Journal Volume: 254 Pages: 105398-105398
  • DOI: 10.1016/j.tvjl.2019.105398
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of a two-base insertion mutation of the TP53 gene on expression of p53 protein in canine histiocytic sarcoma cells. (2019)
  • Author(s): Asada H, Toiyasu H, Goto-Koshino Y, Ohno K, Tsujimoto H
  • Journal Title: Am J Vet Res Volume: 80 Issue: 7 Pages: 680-688
  • DOI: 10.2460/ajvr.80.7.680
  • Peer Reviewed
• [Journal Article] Development of canine X-chromosome inactivation pattern analysis for the detection of cell clonality by incorporating the examination of the SLIT and NTRK-like family member 4 (SLITRK4) gene. (2019)
  • Author(s): Tomita A, Mochizuki H, Tsuboi M, Ogura I, Igarashi H, Goto-Koshino Y, Takahashi M, Ohmi A, Tomiyasu H, Ohno K, Nakagawa T, Uchida K, Nishimura R, Tsujimoto H
  • Journal Title: Res Vet Sci Volume: 125 Pages: 170-175
  • DOI: 10.1016/j.rvsc.2019.06.004
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines. (2019)
  • Author(s): Asada H, Yomiyasu H, Uchikai T, Ishihara G, Goto-Koshino Y, Ohno K, Tsujimoto H
  • Journal Title: PLoS One Volume: 14 Issue: 4 Pages: e0208567-e0208567
  • DOI: 10.1371/journal.pone.0208567
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of cell line and in vivo mouse model of canine Langerhans cell histiocytosis (2019)
  • Author(s): Son Nguyen V.、Uchida Kazuyuki、Thongtharb Atigan、Chambers James K.、Kishimoto Takuya E.、Tomiyasu Hirotaka、Ohmi Aki、Tsujimoto Hajime、Nakayama Hiroyuki
  • Journal Title: Veterinary and Comparative Oncology Volume: - Issue: 3 Pages: 345-353
  • DOI: 10.1111/vco.12476
  • Peer Reviewed
• [Journal Article] Neural anti-inflammatory action mediated by two types of acetylcholine receptors in the small intestine (2019)
  • Author(s): Kimura Hitomi、Imura Yu-ki、Tomiyasu Hirotaka、Mihara Taiki、Kaji Noriyuki、Ohno Koichi、Unno Toshihiro、Tanahashi Yasuyuki、Jan Tong-Rong、Tsubone Hirokazu、Ozaki Hiroshi、Hori Masatoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5887-5887
  • DOI: 10.1038/s41598-019-41698-w
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of the two-base insertion mutation in the TP53 gene in canine histiocytic sarcoma. (2019)
  • Author(s): Asada H, Tomiyasu H, Okada K, Chambers JK, Goto-Koshino Y, Uchida K, Kagawa Y, Ohno K, Tsujimoto H.
  • Journal Title: Res Vet Sci Volume: 124 Pages: 57-60
  • DOI: 10.1016/j.rvsc.2019.03.003
  • Peer Reviewed
• [Journal Article] The intratumor heterogeneity of <i>TP53</i> gene mutations in canine histiocytic sarcoma (2019)
  • Author(s): Asada H, Ichii O, Tomiyasu H, Uchida K, Chambers JK, Goto-Koshino Y, Ohno K, Kon Y, Tsujimoto H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 81 Issue: 3 Pages: 353-356
  • DOI: 10.1292/jvms.18-0419
  • NAID: 130007612993
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and clinicopathological characteristics of acute lymphoblastic leukaemia in six cats. (2018)
  • Author(s): Tomiyasu H, Doi A, Chambers JK, Goto-Koshino Y, Ohmi A, Ohno K, Tsujimoto H.
  • Journal Title: J Small Anim Pract Volume: 59 Issue: 12 Pages: 742-746
  • DOI: 10.1111/jsap.12917
  • Peer Reviewed
• [Journal Article] Prognostic value of CD44 variant isoform expression in dogs with multicentric high-grade B-cell lymphoma. (2018)
  • Author(s): Motegi T, Tomiyasu H, Goto-Koshino Y, Takahashi M, Hiyoshi-Kanemoto S, Fujino Y, Ohno K, Tsuimoto H.
  • Journal Title: Am J Vet Res Volume: 79 Issue: 9 Pages: 961-969
  • DOI: 10.2460/ajvr.79.9.961
  • Peer Reviewed
• [Journal Article] Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq (2018)
  • Author(s): Maeda Shingo、Tomiyasu Hirotaka、Tsuboi Masaya、Inoue Akiko、Ishihara Genki、Uchikai Takao、Chambers James K.、Uchida Kazuyuki、Yonezawa Tomohiro、Matsuki Naoaki
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 472-472
  • DOI: 10.1186/s12885-018-4409-3
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of gene expression profiles reveals novel candidates of chemotherapy resistant factors in canine lymphoma (2017)
  • Author(s): Suenaga, M., Tomiyasu, H., Watanabe, M., Ogawa, K., Motegi, T., Goto-Koshino, Y., Ohno, K., Sugano, S., Skorupski, K.A. and Tsujimoto, H.
  • Journal Title: The Veterinary Journal Volume: 228 Pages: 18-21
  • DOI: 10.1016/j.tvjl.2017.10.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A 2-base insertion in exon 5 is a common mutation of the <i>TP53</i> gene in dogs with histiocytic sarcoma (2017)
  • Author(s): Asada, H., Tsuboi, M., Chambers, J.K., Uchida K., Tomiyasu, H., Goto-Koshino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 79 Issue: 10 Pages: 1721-1726
  • DOI: 10.1292/jvms.17-0197
  • NAID: 130006176479
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Significance of clonal rearrangements of lymphocyte antigen receptor genes on the prognosis of chronic enteropathy in 22 Shiba dogs (2017)
  • Author(s): Ohmi, A., Ohno, K., Uchida, K., Goto-Koshino, Y., Tomiyasu, H., Kanemoto, H., Fikushima, K. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 79 Issue: 9 Pages: 1578-1584
  • DOI: 10.1292/jvms.16-0626
  • NAID: 130006106445
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Presentation] 犬の全血輸血における副反応発生頻度およびその危険因子に関する検討 (2019)
  • Author(s): 谷章禎，富安博隆，大参亜紀，大野耕一，辻本元
  • Organizer: 第16回日本獣医内科学アカデミー学術大会
• [Presentation] 犬リンパ系腫瘍におけるオルサラジンのDNA メチル化阻害作用ならびに抗腫瘍効果 (2019)
  • Author(s): 伊藤智，安達明，山崎淳平，富安博隆，後藤裕子，岡本まり子，岩花倫生，佐原弘益，塚本篤士
  • Organizer: 第16回日本獣医内科学アカデミー学術大会
• [Presentation] リバーロキサバンの投与を行った血栓症の犬23 例の回顧的検討 (2019)
  • Author(s): 福岡玲，大参亜紀，山本貴恵，藤原玲奈，富安博隆，大野耕一，辻本元
  • Organizer: 第16回日本獣医内科学アカデミー学術大会
• [Presentation] Demonstration of clonal hematopoiesis in miniature dachshunds affected with nonregenerative anemia (2019)
  • Author(s): Tani, A、Tomiyasu H、Ohmi A、Ohno K、Tsujimoto H
  • Organizer: Asian Meeting of Animal Medicine Specialties 2019
  • Int'l Joint Research
• [Presentation] Application of a gene expression scoring system to predict chemotherapy sensitivity in canine lymphoma (2019)
  • Author(s): Saegusa Y、Tani A、Ogawa K、Takeuchi Y、Tomiyasu H、Ohno K、Tsujimoto H
  • Organizer: Asian Meeting of Animal Medicine Specialties 2019
  • Int'l Joint Research
• [Presentation] Genetic mutations detected in Miniature Dachshunds diagnosed with myelodysplastic syndrome (MDS) in Japan (2019)
  • Author(s): Tani A、Tomiyasu H、Uchikai T、Matsumoto Y、Ishihara G、Goto-Koshino Y、Ohno K、Tsujimoto H
  • Organizer: American College of Veterinary Internal Medicine Forum 2019
  • Int'l Joint Research
• [Presentation] 犬のランゲルハンス細胞組織球症3 症例における臨床的・病理学的特徴の検討 (2019)
  • Author(s): 横井史花，大参亜紀，チェンバーズ ジェームズ，坪井誠也，内田和幸，富安博隆，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] 犬の大細胞性胃腸管型リンパ腫に対するL- アスパラギナーゼ連続投与の有効性 (2019)
  • Author(s): 小島麻里，中川泰輔，横山 望，大参亜紀，富安博隆，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] 犬メラノーマ細胞株におけるジゴキシンの抗腫瘍効果 (2019)
  • Author(s): 伊藤 智，佐久間百絵，安達 明，山崎淳平，衛藤翔太郎，中川貴之， 富安博隆，納谷裕子，荻原喜久美，猪股智夫，塚本篤士
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] T-cell-rich large B-cell lymphomaの猫の2 例 (2019)
  • Author(s): 菅原芽伊，大参亜紀，佐藤 茜，佐野頼典，坪井誠也，チェンバーズ・ジェームズ， 内田和幸，富安博隆，後藤（越野）裕子，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] 犬の大細胞性消化器型リンパ腫に関連した消化管穿孔に関する回顧的研究 (2019)
  • Author(s): 杉浦 叶，中川泰輔，横山 望，大参亜紀，富安博隆，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] Comprehensive analysis of gene mutation in canine histiocytic sarcoma by whole exome sequencing (2018)
  • Author(s): Hajime Asada, Takao Uchikai, Hirotaka Tomiyasu, Genki Ishihara, Yuko Goto-Koshino, Koichi Ohno, Hajime Tsujimoto
  • Organizer: American College of Veterinary Internal Medicine Forum
  • Int'l Joint Research
• [Presentation] イヌDLBCLにおけるゲノムワイドDNAメチル化パターンと予後との関連 (2018)
  • Author(s): 久本真也、山崎淳平、茂木朋貴、富安博隆、後藤（越野）裕子、辻本元、稲葉睦
  • Organizer: 第14回日本獣医内科学アカデミー学術大会
• [Presentation] ジャックラッセルテリアにおける消化管腺癌の臨床的特徴と予後 (2018)
  • Author(s): 大参亜紀、大野耕一、横山望、中川泰輔、富安博隆、チェンバーズ・ジェームズ、内田和幸、辻本元
  • Organizer: 第14回日本獣医内科学アカデミー学術大会
• [Presentation] A 2-Base Insertion Mutation of TP53 Gene and its Intratumor Heterogeneity in Canine Histiocytic Sarcoma (2017)
  • Author(s): Asada Hajime, Ichii Osamu, Tomiyasu Hirotaka, Tsuboi Masaya, Uchida Kazuyuki, Goto-Koshino Yuko, Ohno Koichi, Kon Yasuhiro, Tsujimoto Hajime
  • Organizer: Veterinary Cancer Society Annual Conference 2017
  • Int'l Joint Research
• [Presentation] A Gene Expression Scoring System to Predict Chemotherapy Resistance Using Novel Drug Resistance Factors in Canine Lymphoma (2017)
  • Author(s): Ogawa Kotoko, Tomiyasu Hirotaka, Suenaga Miyu, Watanabe Manabu, Sugano Sumio, Motegi Tomoki, Takeuchi Yoshinori, Omi Aki, Goto-Koshino Yuko, Ohno Koichi, Skorupski Katherine, Tsujimoto Hajime
  • Organizer: Veterinary Cancer Society Annual Conference 2017
  • Int'l Joint Research
• [Remarks] 東京大学 獣医内科学教室 血液・腫瘍性疾患 研究チーム
  • URL: https://www.vetinternmed-oncology.com