Comprehensive analysis of molecular mechanisms of drug resistance in canine malignant tumors

• Project/Area Number: 26292158
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: The University of Tokyo
• Principal Investigator: Tsujimoto Hajime 東京大学, 農学生命科学研究科, 教授 (60163804)
• Co-Investigator(Kenkyū-buntansha): 渡邊 学 東京大学, 新領域創成科学研究科, 准教授 (70376606)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 犬 / 悪性腫瘍 / 薬剤耐性 / 網羅的解析

Outline of Final Research Achievements

Drug resistance is a major cause of the failure in the chemotherapy for malignant tumors in dogs. In this study, comprehensive analysis of gene expression profiles revealed that immune responses and inflammatory reactions were suppressed in lymphoma tissues at the acquisition of drug resistance. In addition, a model to predict chemotherapy resistance was established using expression profiles of 6 genes associated with immune/inflammatory responses. This study revealed novel mechanisms of chemotherapy resistance and suggested that the resistance to chemotherapy could be predicted by the quantification of the 6 genes before chemotherapy. Findings obtained from this study would be beneficial for the chemotherapy in dogs and also provide useful information for the cancer chemotherapy in humans.

Research Products

• [Int'l Joint Research] University of California, Davis/School of Veterinary Medicine(米国)
• [Journal Article] Minimal residual disease in canine lymphoma: An objective marker to assess tumor cell burden in remission. (2016)
  • Author(s): Sato, M., Yamazaki, J., Goto-Koshino, Y., Setoguchi, A., Takahashi, M., Baba, K., Fujino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: The Veterinary Journal Volume: 215 Pages: 38-42
  • DOI: 10.1016/j.tvjl.2016.05.012
  • Peer Reviewed
• [Journal Article] Clinical and histopathological evaluation of 16 dogs with T-zone lymphoma. (2016)
  • Author(s): Mizutani, N., Goto-Koshino, Y., Uchida, K., Takahashi, M. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Sciences Volume: 78 Pages: 1237-1244
  • NAID: 130005261545
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive genomic characterization of five canine lymphoid tumor cell lines. (2016)
  • Author(s): Roode, S.C., Rotroff, D., Richards, K.L., Moore, P., Motsinger-Reif, A., Okamura, Y., Mizuno, T., Tsujimoto, H., Suter, S.E. and Breen, M.
  • Journal Title: BMC Veterinary Research Volume: in press Issue: 1
  • DOI: 10.1186/s12917-016-0836-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutation of p53 gene and its correlation with the clinical outcome in dogs with lymphoma. (2016)
  • Author(s): Koshino, A., Goto-Koshino, Y., Setoguchi, A., Ohno, K. and Tsujimoto, H.
  • Journal Title: J. Vet. Intern. Med. Volume: 30 Issue: 1 Pages: 223-229
  • DOI: 10.1111/jvim.13807
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Detection of circulating tumor cells using GeneScan analysis for antigen receptor gene rearrangements in canine lymphoma patients (2016)
  • Author(s): Hiyoshi-Kanemoto, S., Goto-Koshino, Y., Fukushima, K., Takahashi, M., Kanemoto, H., Uchida, K., Fujino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 78 Issue: 5 Pages: 877-881
  • DOI: 10.1292/jvms.15-0433
  • NAID: 130005154308
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Evaluation of CD25-positive cells in relation to the subtypes and prognoses in various lymphoid tumours in dogs. (2016)
  • Author(s): Mizutani, N., Goto-Koshino, Y., Tsuboi, M., Kagawa, Y., Ohno, K., Uchida, K. and Tsujimoto, H.
  • Journal Title: Vet. Immunol. Immunopathol. Volume: 167 Pages: 39-43
  • DOI: 10.1016/j.vetimm.2016.03.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evaluation of the drug sensitivity and expression of 16 drug resistance-related genes in canine histiocytic sarcoma cell lines (2015)
  • Author(s): Asada, H., Tomiyasu, H., Goto-Koshino, Y., Fujino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 77 Issue: 6 Pages: 677-684
  • DOI: 10.1292/jvms.14-0415
  • NAID: 130005085856
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comparative aspects of molecular mechanisms of drug resistance through ABC transporters and other related molecules in canine lymphoma. (2015)
  • Author(s): Tomiyasu, H. and Tsujimoto, H.
  • Journal Title: Vet. Sci. Volume: 2 Issue: 3 Pages: 28-32
  • DOI: 10.3390/vetsci2030185
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Construction of a multicolor GeneScan analytical system to detect clonal rearrangements of immunoglobulin and T cell receptor genes in canine lymphoid tumors. (2015)
  • Author(s): Goto-Koshino, Y., Mochizuki, H., Sato, M., Nakashima, K., Hiyoshi, S., Fujiwara-Igarashi, A., Maeda, S., Nakamura, K., Uchida, K., Fujino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: Veterinary Immunology and Immunopathology Volume: In press Issue: 1-2 Pages: 81-87
  • DOI: 10.1016/j.vetimm.2015.03.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypermethylation of the death-associated protein kinase CpG island in canine B-cell lymphoid tumors. (2014)
  • Author(s): Sato, M., Mochizuki, H., Goto-Koshino, Y., Fujiwara-Igarashi, A., Takahashi, M., Fujino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: Veterinary Immunology and Immunopathology Volume: 161 Issue: 3-4 Pages: 222-231
  • DOI: 10.1016/j.vetimm.2014.08.011
  • Peer Reviewed / Open Access
• [Presentation] 全エクソームシークエンシングを用いた犬の多中心型高悪性度B細胞性リンパ腫における生殖細胞系列変異の検出 (2017)
  • Author(s): 茂木朋貴、富安博隆、後藤（越野）裕子、金本英之、大野耕一、渡邊学、菅野純夫、辻本元
  • Organizer: 第13回日本獣医内科学アカデミー学術大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2017-02-17
• [Presentation] 犬の組織球性肉腫において高頻度に認められたTP53遺伝子における2塩基挿入 (2017)
  • Author(s): 浅田創、坪井誠也、内田和幸、富安博隆、大参亜紀、金本英之、後藤（越野）裕子、大野耕一、辻本元
  • Organizer: 第13回日本獣医内科学アカデミー学術大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2017-02-17
• [Presentation] 犬の多中心型高悪性度B細胞リンパ腫における新規化学療法耐性化因子の発現量解析 (2017)
  • Author(s): 小川琴子、富安博隆、末永珠佑、渡邊学、菅野純夫、茂木朋貴、大参亜紀、後藤（越野）裕子、大野耕一、Skorupski A Katherine、辻本元
  • Organizer: 第13回日本獣医内科学アカデミー学術大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2017-02-17
• [Presentation] Prognostic significance of the expression of CD44 variant isoform in canine multicentric high-grade B-cell lymphoma (2016)
  • Author(s): Motegi Tomoki, Tomiyasu Hirotaka, Goto-Koshino Yuko, Ohno Koichi, Tsujimoto Hajime
  • Organizer: Veterinary Cancer Society Annual Conference
  • Place of Presentation: Orlando, Florida
  • Year and Date: 2016-10-20
  • Int'l Joint Research
• [Presentation] Comprehensive gene expression analysis to elucidate common molecular mechanism of drug resistance in canine lymphoma (2016)
  • Author(s): Tomiyasu Hirotaka, Suenaga Miyu, Watanabe Manabu, Ogawa Kotoko, Motegi Tomoki, Goto-Koshino Yuko, Ohno Koichi, Sugano Sumio, Skorupski A. Katherine, Tsujimoto Hajime
  • Organizer: Veterinary Cancer Society Annual Conference
  • Place of Presentation: Orland, Florida
  • Year and Date: 2016-10-20
  • Int'l Joint Research
• [Presentation] 犬のリンパ腫における化学療法耐性化関連遺伝子群の網羅的解析 (2016)
  • Author(s): 末永珠佑、富安博隆、渡邊学、後藤（越野）裕子、大野耕一、菅野純夫、辻本元
  • Organizer: 第12回日本獣医内科学アカデミー学術大会
  • Place of Presentation: 横浜市（神奈川県）
  • Year and Date: 2016-02-19
• [Presentation] 犬のリンパ腫においてCD44バリアントアイソフォームの発現が予後に与える影響 (2015)
  • Author(s): 茂木朋貴、高橋雅、富安博隆、越野（後藤）裕子、大野耕一、辻本元
  • Organizer: 第158回日本獣医学会学術集会
  • Place of Presentation: 十和田市（青森県）
  • Year and Date: 2015-09-07
• [Presentation] 犬のB細胞性高悪性度リンパ腫における網羅的遺伝子発現量解析による化学療法感受性関連遺伝子群の探索 (2015)
  • Author(s): 末永珠佑、富安博隆、渡邊学、越野（後藤）裕子、大野耕一、菅野純夫、辻本元
  • Organizer: 第11回日本獣医内科学アカデミー学術大会
  • Place of Presentation: パシフィコ横浜、横浜、神奈川
  • Year and Date: 2015-02-20 – 2015-02-22
• [Presentation] 伴侶動物の乳腺腫瘍へのラパチ二ブ投与における分子生物学的解析およびトランスレーショナルリサーチの試み (2014)
  • Author(s): 渡邊学、木村絵里、坪井誠也、萱橋賭朋子、今村昌平、佐伯亘平、中川貴之、内田和幸、望月学、西村亮平、辻本元、菅野純夫
  • Organizer: 第157回日本獣医学会学術集会
  • Place of Presentation: 北海道大学、札幌、北海道
  • Year and Date: 2014-09-09 – 2014-09-12