Development of a diagnostic model for a risk of colorectal cancer recurrence

• Project/Area Number: 16KT0116
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Ueda Koji 公益財団法人がん研究会, がんプレシジョン医療研究センター がんオーダーメイド医療開発プロジェクト, プロジェクトリーダー (10509110)
• Co-Investigator(Kenkyū-buntansha): 長山 聡 公益財団法人がん研究会, 有明病院 消化器外科, 医長 (70362499)
• Project Period (FY): 2016-07-19 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: バイオマーカー / 大腸癌 / プロテオミクス / 大腸がん / 腫瘍マーカー

Outline of Final Research Achievements

To develop a novel diagnostic model for early recurrence of colorectal cancer, comprehensive proteomic analysis of tissue and plasma samples was performed. Comparative analysis between the early recurrence group and recurrence-free group identified 81 tissue proteins and 37 plasma proteins as the predictive biomarker candidates. Next, based on mass spectrometric absolute quantification analysis and the Error rate monitoring test, 4 plasma proteins were determined to be the least set for most effective classification of 2 groups. Finally, the logistic regression model using pre-operative levels of these 4 plasma proteins accurately predicted the high-risk group of colorectal cancer recurrence.

Academic Significance and Societal Importance of the Research Achievements

本邦において大腸がんは部位別がん罹患数で1位、死亡数で2位を占める。集学的治療法の発展に伴って予後の改善は見られているものの、臨床病期II期、III期の手術後再発例は予後が不良である。したがってこれら再発高リスク群を正確に特定し、術後補助化学療法など適切なコントロールを行うことができれば、有意な予後の改善が期待できる。本研究開発では最終的に治療前における4種の血漿中タンパク質濃度を用いれば極めて高精度な大腸がん術後再発高危険度群を予測できるモデルを構築できた。低侵襲な当血液診断によって低リスク群には不要な化学療法を回避し、高リスク群には積極的な加療を行うなど個別化医療に資する成果といえる。

Research Products

• [Journal Article] Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice (2020)
  • Author(s): Yamaguchi Takefumi、Higa Kazunari、Yagi-Yaguchi Yukari、Ueda Koji、Noma Hisashi、Shibata Shinsuke、Nagai Toshihiro、Tomida Daisuke、Yasu-Mimura Ririko、Ibrahim Osama、Matoba Ryo、Tsubota Kazuo、Hamrah Pedram、Yamada Jun、Kanekura Kohsuke、Shimazaki Jun
  • Journal Title: Science Advances Volume: 6 Issue: 20 Pages: 5195-5195
  • DOI: 10.1126/sciadv.aaz5195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolites Interrogation in Cell Fate Decision of Cultured Human Corneal Endothelial Cells (2020)
  • Author(s): Hamuro Junji、Numa Kohsaku、Fujita Tomoko、Toda Munetoyo、Ueda Koji、Tokuda Yuichi、Mukai Atushi、Nakano Masakazu、Ueno Morio、Kinoshita Shigeru、Sotozono Chie
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 61 Issue: 2 Pages: 10-10
  • DOI: 10.1167/iovs.61.2.10
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proteomic Analysis of Extracellular Vesicles for Cancer Diagnostics. (2019)
  • Author(s): Wu, A.Y., Ueda, K., and Lai, C.P.
  • Journal Title: Proteomics Volume: 19 Issue: 1-2 Pages: 1800162-1800162
  • DOI: 10.1002/pmic.201800162
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prospective exosome-focused translational research for afatinib study of non-small cell lung cancer patients expressing EGFR (EXTRA study) (2019)
  • Author(s): Okuma, Y., Morikawa, K., Tanaka, H., Yokoyama, T., Itani, H., Horiuchi, K., Nakagawa, H., Takahashi, N., Bessho, A., Soejima, K., Kishi, K., Togashi, A., Kanai, Y., Ueda, K., Horimoto, K., Matsutani, N., and Seki, N.
  • Journal Title: Thorac Cancer Volume: 10 Issue: 2 Pages: 395
  • DOI: 10.1111/1759-7714.12923
  • URL: https://pure.teikyo.jp/en/publications/975bcf2a-0cc7-4e71-8f24-ce6c95120e5e
  • Peer Reviewed
• [Journal Article] INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4. (2019)
  • Author(s): Liu, Y.Y., Tanikawa, C., Ueda, K., and Matsuda, K.
  • Journal Title: International journal of oncology Volume: 54 Pages: 1907-1920
  • DOI: 10.3892/ijo.2019.4786
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Leukocyteassociated immunoglobulinlike receptor 1 promotes tumorigenesis in RCC (2019)
  • Author(s): Jingushi, K., Uemura, M., Nakano, K., Hayashi, Y., Wang, C., Ishizuya, Y., Yamamoto, Y., Hayashi, T., Kinouchi, T., Matsuzaki, K., Kato, T., Kawashima, A., Ujike, T., Nagahara, A., Fujita, K., Ueda, K., Tsujikawa, K., and Nonomura, N.
  • Journal Title: Oncol Rep Volume: 41 Pages: 1293-1303
  • DOI: 10.3892/or.2018.6875
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Multisialylated LacdiNAc Structures as Highly Prostate Cancer Specific Glycan Signatures on PSA. (2019)
  • Author(s): Haga, Y., Uemura, M., Baba, S., Inamura, K., Takeuchi, K., Nonomura, N., and Ueda, K.
  • Journal Title: Analytical chemistry Volume: 91 Issue: 3 Pages: 2247-2247
  • DOI: 10.1021/acs.analchem.8b04829
  • Peer Reviewed
• [Journal Article] Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility (2018)
  • Author(s): Tanikawa Chizu、Ueda Koji、Suzuki Akari、Iida Aritoshi、Nakamura Ryoichi、Atsuta Naoki、Tohnai Genki、Sobue Gen、Saichi Naomi、Momozawa Yukihide、Kamatani Yoichiro、Kubo Michiaki、Yamamoto Kazuhiko、Nakamura Yusuke、Matsuda Koichi
  • Journal Title: Cell Reports Volume: 22 Issue: 6 Pages: 1473-1483
  • DOI: 10.1016/j.celrep.2018.01.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells. (2018)
  • Author(s): Deng, B., Tarhan, Y.E., Ueda, K., Ren, L., Katagiri, T., Park, J.H., and Nakamura, Y.
  • Journal Title: Neoplasia Volume: 20 Issue: 10 Pages: 1038-1044
  • DOI: 10.1016/j.neo.2018.08.006
  • NAID: 120007027664
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular vesicles isolated from human renal cell carcinoma tissues disrupt vascular endothelial cell morphology via azurocidin (2017)
  • Author(s): Jingushi Kentaro、Uemura Motohide、Ohnishi Naomi、Nakata Wataru、Fujita Kazutoshi、Naito Takuya、Fujii Risa、Saichi Naomi、Nonomura Norio、Tsujikawa Kazutake、Ueda Koji
  • Journal Title: International Journal of Cancer Volume: 142 Issue: 3 Pages: 607-617
  • DOI: 10.1002/ijc.31080
  • Peer Reviewed / Open Access
• [Journal Article] p53-independent p21 induction by MELK inhibition (2017)
  • Author(s): Matsuda Tatsuo、Kato Taigo、Kiyotani Kazuma、Tarhan Yunus Emre、Saloura Vassiliki、Chung Suyoun、Ueda Koji、Nakamura Yusuke、Park Jae-Hyun
  • Journal Title: Oncotarget Volume: 8 Issue: 35 Pages: 57938-57947
  • DOI: 10.18632/oncotarget.18488
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of tubular recycling endosome biogenesis by the p53-MICALL1 pathway (2017)
  • Author(s): Takahashi Yukie、Tanikawa Chizu、Miyamoto Takafumi、Hirata Makoto、Wang Guanxiong、Ueda Koji、Komatsu Tsunehiko、Matsuda Koichi
  • Journal Title: International Journal of Oncology Volume: 51 Issue: 2 Pages: 724-736
  • DOI: 10.3892/ijo.2017.4060
  • Peer Reviewed
• [Journal Article] Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53 (2017)
  • Author(s): Miyamoto Takafumi、Lo Paulisally Hau Yi、Saichi Naomi、Ueda Koji、Hirata Makoto、Tanikawa Chizu、Matsuda Koichi
  • Journal Title: Science Advances Volume: 3 Issue: 5 Pages: 1603204-1603204
  • DOI: 10.1126/sciadv.1603204
  • Peer Reviewed / Open Access
• [Journal Article] Effects of SMYD2-mediated EML4-ALK methylation on the signaling pathway and growth in non-small cell lung cancer cells (2017)
  • Author(s): Wang, R., Deng, X., Yoshioka, Y., Vougiouklakis, T., Park, J. H., Suzuki, T., Dohmae, N., Ueda, K., Hamamoto, R. and Nakamura, Y.
  • Journal Title: Cancer Science Volume: in press Issue: 6 Pages: 1203-1209
  • DOI: 10.1111/cas.13245
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MiR-21-5p in urinary extracellular vesicles is a novel biomarker of urothelial carcinoma. (2017)
  • Author(s): Matsuzaki K et al.
  • Journal Title: Oncotarget Volume: - Issue: 15 Pages: 14969-14969
  • DOI: 10.18632/oncotarget.14969
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] EPSIN 3, A Novel p53 Target, Regulates the Apoptotic Pathway and Gastric Carcinogenesis. (2017)
  • Author(s): Mori J, Tanikawa C, Ohnishi N, Funauchi Y, Toyoshima O, Ueda K, Matsuda K.
  • Journal Title: Neoplasia Volume: 19 Issue: 3 Pages: 185-195
  • DOI: 10.1016/j.neo.2016.12.010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] GALNT6 Stabilizes GRP78 Protein by O-glycosylation and Enhances its Activity to Suppress Apoptosis Under Stress Condition. (2017)
  • Author(s): Lin J, Chung S, Ueda K, Matsuda K, Nakamura Y, Park JH.
  • Journal Title: Neoplasia Volume: 19 Issue: 1 Pages: 43-53
  • DOI: 10.1016/j.neo.2016.11.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53 (2017)
  • Author(s): Miyamoto, T., Lo, PHY., Saichi, N., Ueda, K., Hirata, M., Tanikawa, C. Matsuda, K.
  • Journal Title: Science Advances Volume: in press
  • Peer Reviewed
• [Journal Article] Exosomal microRNA miR-1246 induces cell motility and invasion through the regulation of DENND2D in oral squamous cell carcinoma. (2016)
  • Author(s): Sakha S, Muramatsu T, Ueda K, Inazawa J:
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 38750-38750
  • DOI: 10.1038/srep38750
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors (2016)
  • Author(s): Nakakido, M., Tamura, K., Chung, S., Ueda, K., Fujii, R., Kiyotani, K. and Nakamura, Y.
  • Journal Title: International Journal of Oncology Volume: 49 Issue: 3 Pages: 868-876
  • DOI: 10.3892/ijo.2016.3607
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Morphological Changes, Cadherin Switching, and Growth Suppression in Pancreatic Cancer by GALNT6 Knockdown (2016)
  • Author(s): Tarhan, Y. E., Kato, T., Jang, M., Haga, Y., Ueda, K., Nakamura, Y. and Park, J. H.
  • Journal Title: Neoplasia Volume: 18 Issue: 5 Pages: 265-72
  • DOI: 10.1016/j.neo.2016.03.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exosomes as nanocarriers for systemic delivery of the Helicobacter pylori virulence factor CagA (2016)
  • Author(s): Shimoda A, Ueda K, Nishiumi S, Murata-Kamiya N, Mukai SA, Sawada S, Azuma T, Hatakeyama M, Akiyoshi K
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 18346-18346
  • DOI: 10.1038/srep18346
  • NAID: 120005689168
  • Peer Reviewed / Open Access
• [Presentation] Quantitative proteomic profiling of tissue-exudative EVs identified an early diagnostic biomarker protein for colorectal cancer (2019)
  • Author(s): Makoto Konishi, Makoto Sumazaki, Satoshi Muraoka, Atsushi Ikeda, Risa Fujii, Naomi Saichi, Hideaki Shimada, Satoshi Nagayama, Koji Ueda
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Development of novel EV-based biomarker for colorectal cancer and its physiological role for angiogenesis (2019)
  • Author(s): Atsushi Ikeda, Satoshi Nagayama, Koji Ueda
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Proteome-wide profiling of viable tissue-derived exosomes, toward development of cancer liquid biopsy (2019)
  • Author(s): Koji Ueda
  • Organizer: Inaugural Annual Meeting of Asian Pacific Societies for Extracellular Vesicles
  • Int'l Joint Research / Invited
• [Presentation] A Proteome-wide Catalog of Viable Tissue-derived Exosomes, Toward Development of Cancer Liquid Biopsy (2019)
  • Author(s): 植田幸嗣
  • Organizer: 11th AACR-JCA Joint Conference
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of a proteomic contexture of exosomes for development of cancer early detection diagnostics (2018)
  • Author(s): 植田幸嗣
  • Organizer: 第77回日本癌学会学術総会
  • Invited
• [Presentation] Development of liquid biopsy diagnostics for colorectal cancer by proteomic profiling of cultured tissue-derived exosome (2018)
  • Author(s): 池田篤志、長山聡、植田幸嗣
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Identification of a novel diagnostic antigen on circulating exosomes, toward sensitive early detection of colon cancer (2018)
  • Author(s): 小西惇、須磨崎真、長山聡、植田幸嗣
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] エクソソームを利用した大腸がんリキッドバイオプシーの開発 (2018)
  • Author(s): 植田幸嗣
  • Organizer: 第56回日本癌治療学会学術集会
  • Invited
• [Presentation] Elucidation of tumor microenvironment networks by in-depth proteome analysis of extracellular vesicles (2018)
  • Author(s): Ueda, K.
  • Organizer: The 33rd Joint Annual Conference of Biomedical Science
  • Int'l Joint Research / Invited
• [Presentation] Proteomic profiling of exosomes isolated from viable renal cell carcinoma tissues, toward development of cancer liquid biopsy diagnostics (2018)
  • Author(s): Ueda, K.
  • Organizer: US-Japan Workshop for Cancer Research ～Biomarker Discovery for Early Cancer Detection～
  • Int'l Joint Research / Invited
• [Presentation] 大腸癌切除組織と組織培養分泌エクソソームの網羅的プロテオーム比較分析による大腸癌リキッドバイオプシー診断法開発 (2017)
  • Author(s): 村岡賢, 大西なおみ, 池田篤志, 須磨崎真, 長山聡, 植田幸嗣
  • Organizer: 日本細胞外小胞学会2017年年会
• [Presentation] エクソソームの高深度プロテオミクス解析による癌微小環境ネットワークの解明 (2017)
  • Author(s): 植田幸嗣
  • Organizer: ConBio2017
  • Invited
• [Presentation] エクソソームを標的とした新しい臨床検査 (2017)
  • Author(s): 植田幸嗣
  • Organizer: 第68回日本電気泳動学会総会
  • Invited
• [Presentation] エクソソーム表面抗原を標的とした腫瘍マーカー開発 (2017)
  • Author(s): 植田幸嗣
  • Organizer: 第37回日本分子腫瘍マーカー研究会
  • Invited
• [Presentation] エクソソーム解析 (2017)
  • Author(s): 植田幸嗣
  • Organizer: 日本プロテオーム学会2017年年会
  • Invited
• [Presentation] バイオマーカー研究の最前線 (2017)
  • Author(s): 植田幸嗣
  • Organizer: 第32回日本肺癌学会ワークショップ
  • Invited
• [Presentation] A proteome-wide catalog of extracellular vesicles, toward development of cancer liquid biopsy diagnostics (2017)
  • Author(s): Ueda, K.
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] Proteome-wide profiling of exosomes revealed exosome-driven intercellular communications in gastric cancer microenvironment and macroenvironment (2017)
  • Author(s): Ueda, K.
  • Organizer: HUPO 2017
  • Int'l Joint Research
• [Presentation] Comprehensive EV proteomics revealed EV-driven intercellular communications in gastric cancer microenvironment and macroenvironment (2017)
  • Author(s): Ohnishi, N., Saichi, N., Fujii, R., Murakami, K., Matsubara, H., and Ueda, K.
  • Organizer: The International Society For Extracellular Vesicles 6th Annual Meeting
  • Int'l Joint Research
• [Presentation] Proteome-wide profiling of viable tissue-derived extracellular vesicles for development of early diagnostic biomarkers for colorectal cancer (2017)
  • Author(s): Muraoka, S., Nagayama, S., and Ueda, K.
  • Organizer: The International Society For Extracellular Vesicles 6th Annual Meeting
  • Int'l Joint Research
• [Presentation] 細胞外分泌小胞エクソソームによるがん診断 (2017)
  • Author(s): Koji Ueda
  • Organizer: 第17回関東ホルモンと癌研究会
  • Place of Presentation: Osaka
  • Invited
• [Presentation] Exosomal Liquid Biopsy for Early Detection of Kidney Cancer (2017)
  • Author(s): Koji Ueda
  • Organizer: The 4th Annual US Japan Workshop on Cancer Biomarkers
  • Place of Presentation: Tempe, AZ, USA
  • Int'l Joint Research / Invited
• [Presentation] Microenvironmental communications within gastrointestinal cancer tissue illustrated by proteome analysis of exosomes (2016)
  • Author(s): Koji Ueda
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: Tokyo
  • Year and Date: 2016-10-06
• [Presentation] Development of personalized cancer immunotherapy by Trans-OMICS analysis (2016)
  • Author(s): Koji Ueda
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: Kobe
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] Proteogenomic profiling of neoantigens for personalized cancer immunotherapy (2016)
  • Author(s): Koji Ueda
  • Organizer: Human Proteome Organization 2016
  • Place of Presentation: Taipei
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Trans-OMICS analysis of immunopeptidome for development of personalized cancer immunotherapy (2016)
  • Author(s): Koji Ueda
  • Organizer: 日本プロテオーム学会2016年年会
  • Place of Presentation: Tokyo
  • Year and Date: 2016-07-28
  • Invited
• [Presentation] エクソソームを利用したがん早期診断法の開発 (2016)
  • Author(s): Koji Ueda
  • Organizer: 第23回JBICバイオ関連基盤技術研究会
  • Place of Presentation: Tokyo
  • Invited
• [Book] 実験医学 2017年6月号 (2017)
  • Author(s): 植田 幸嗣
  • Total Pages: 141
  • Publisher: 羊土社
  • ISBN: 4758101647
• [Book] 腎臓内科・泌尿器科 第6巻第6号 (2017)
  • Author(s): 植田 幸嗣
  • Total Pages: 74
  • Publisher: 科学評論社
• [Book] 実験医学 2016年6月号 Vol.34 No.9 (2016)
  • Author(s): 植田幸嗣
  • Total Pages: 141
  • Publisher: 羊土社