Proteomic study using clinical materials for metastatic bone tumor toward the understanding of molecular backgrounds and the development of novel therapy

• Project/Area Number: 16K10880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kondo Tadashi 国立研究開発法人国立がん研究センター, 研究所, 分野長 (30284061)
• Co-Investigator(Kenkyū-buntansha): 穴澤 卯圭 東京歯科大学, 歯学部, 教授 (20245525) ; 菊田 一貴 東京歯科大学, 歯学部, 非常勤講師 (30383798) ; 多田 裕司 千葉大学, 大学院医学研究院, 特任教授 (50344990) ; 川井 章 国立研究開発法人国立がん研究センター, 中央病院, 科長 (90252965)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 転移性骨腫瘍 / バイオマーカー / プロテオーム解析 / プロテオーム / PDX

Outline of Final Research Achievements

This study was conducted to understanding of disease mechanisms of metastatic bone tumors, and to develop biomarkers. This study was characterized by the use of clinical specimens and proteomics data. Large-format two-dimensional difference gel electrophoresis and mass spectrometry were employed in this study. We created the protein expression profiles of metastatic tumors, identifying the proteins unique to tumors, and found biomarker candidates as proteins which could be released from the tumors and exist in the blood stream. Using the plasma samples, we validated the presence of identified proteins in the patients with or without bone metastasis. In addition, we investigated the protein expression differences among the metastatic bone tumors with different original sites. Those proteins could be candidates of biomarkers for differential diagnosis of malignancies of unknown origin.

Academic Significance and Societal Importance of the Research Achievements

骨は肺に次いで転移の多い臓器であり、多くの悪性腫瘍は骨に転移する。骨転移は予後不良因子であり、病的骨折を来すなどして患者のQOLを著しく損なう。しかしながら、転移性骨腫瘍の早期診断や有効な治療法は限られている。高齢化に伴うがん患者の増加および治療法の進歩により、骨に転移をもって長期生存する症例は増えており、転移性骨腫瘍の治療法の開発はますます重要になっている。その原発腫瘍の性状や分子背景により、転移性骨腫瘍は複雑な病態を示すが、適切な実験モデルが得難い。臨床検体を用いたオミクス解析のデータによって分子背景を網羅的に理解することで、有用なバイオマーカーなど新しい発見を期待することができる。

Research Products

• [Int'l Joint Research] HudsonAlpha Institute for Biotechnology(米国)
• [Journal Article] Cancer biomarker development and two-dimensional difference gel electrophoresis (2D-DIGE) (2019)
  • Author(s): Kondo T
  • Journal Title: Biochim Biophys Acta Proteins Proteom Volume: 1867 Issue: 1 Pages: 2-2
  • DOI: 10.1016/j.bbapap.2018.07.002
  • Peer Reviewed
• [Journal Article] Decorin as a prognostic biomarker in patients with malignant peripheral nerve sheath tumors (2019)
  • Author(s): Jia Xiaotian、Chen Chao、Chen Lin、Yu Cong、Kondo Tadashi
  • Journal Title: Oncology Letters Volume: 17 Pages: 3517-3522
  • DOI: 10.3892/ol.2019.9959
  • Peer Reviewed / Open Access
• [Journal Article] Calreticulin as A Novel Potential Metastasis-Associated Protein in Myxoid Liposarcoma, as Revealed by Two-Dimensional Difference Gel Electrophoresis (2019)
  • Author(s): Tajima Takashi、Kito Fusako、Yoshida Akihiko、Kawai Akira、Kondo Tadashi
  • Journal Title: Proteomes Volume: 7 Issue: 2 Pages: 13-13
  • DOI: 10.3390/proteomes7020013
  • Peer Reviewed / Open Access
• [Journal Article] A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes. (2019)
  • Author(s): Asano N, Matsuzaki J, Ichikawa M, Kawauchi J, Takizawa S, Aoki Y, Sakamoto H, Yoshida A, Kobayashi E, Tanzawa Y, Nakayama R, Morioka H, Matsumoto M, Nakamura M, Kondo T, Kato K, Tsuchiya N, Kawai A, Ochiya T
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1299-1299
  • DOI: 10.1038/s41467-019-09143-8
  • Peer Reviewed / Open Access
• [Journal Article] Screening of a growth inhibitor library of sarcoma cell lines to identify potent anti-cancer drugs. (2019)
  • Author(s): Qiao Z, Kondo T
  • Journal Title: J Electrophoresis Volume: 63 Pages: 1-7
  • NAID: 130007594658
  • Peer Reviewed
• [Journal Article] HDAC2 regulates site-specific acetylation of MDM2 and its ubiquitination signaling in tumor suppression. (2019)
  • Author(s): Patel N, Wang J, Shiozawa K, Jones KB, Zhang Y, Prokop JW, Davenport GG, Nihira NT, Hao Z, Wong D, Brandsmeier L, Meadows SK, Sampaio AV, Werff RV, Endo M, Capecchi MR, McNagny KM, Mak TW, Nielsen TO, Underhill TM, Myers RM, Kondo T, Su L.
  • Journal Title: iSci Volume: Feb 15
  • Peer Reviewed
• [Journal Article] Current Status of Proteomics in Ewing's Sarcoma (2018)
  • Author(s): Kondo T
  • Journal Title: Proteomics Clin Appl Volume: e1700130 Issue: 3
  • DOI: 10.1002/prca.201700130
  • Peer Reviewed
• [Journal Article] Meta-analysis of global gene-expression profiles identify molecular signatures for histological subtypes of sarcomas (2018)
  • Author(s): Qiao Z, Parlayan C, Saito S, Kondo T
  • Journal Title: Journal of Electrophoresis Volume: 62 Issue: 1 Pages: 21-29
  • DOI: 10.2198/jelectroph.62.21
  • NAID: 130007546308
  • ISSN: 1349-9394, 1349-9408
  • Peer Reviewed
• [Journal Article] Pazopanib-induced changes in protein expression signatures of extracellular vesicles in synovial sarcoma (2018)
  • Author(s): Shiozawa Kumiko、Yoshioka Yusuke、Qiao Zhiwei、Shuting Ji、Ochiya Takahiro、Kondo Tadashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 506 Issue: 3 Pages: 723-730
  • DOI: 10.1016/j.bbrc.2018.10.012
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and proteomic characterization of a novel cell line, NCC-UPS2-C1, derived from a patient with undifferentiated pleomorphic sarcoma (2018)
  • Author(s): Oyama R, Kito F, Sakumoto M, Shiozawa K, Toki S, Yoshida A, Kawai A, Kondo T.
  • Journal Title: In Vitro Cell Dev Biol Anim Volume: 54 Issue: 3 Pages: 257-263
  • DOI: 10.1007/s11626-018-0229-7
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and proteomic characterization of patient-derived clear cell sarcoma xenografts and cell lines (2018)
  • Author(s): Sakumoto M, Oyama R, Takahashi M, Takai Y, Kito F, Shiozawa K, Qiao Z, Endo M, Yoshida A, Kawai A, Kondo T
  • Journal Title: In Vitro Cell Dev Biol Anim Volume: 54 Issue: 2 Pages: 163-176
  • DOI: 10.1007/s11626-017-0207-5
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicle-encapsulated microRNA-761 enhances pazopanib resistance in synovial sarcoma (2018)
  • Author(s): Shiozawa K, Shuting J, Yoshioka Y, Ochiya T, Kondo T.
  • Journal Title: Biochem Biophys Res Commun Volume: 495 Issue: 1 Pages: 1322-1327
  • DOI: 10.1016/j.bbrc.2017.11.164
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of a patient-derived cancer model of undifferentiated pleomorphic sarcoma (2017)
  • Author(s): Kito F, Oyama R, Takahashi M, Shiozawa K, Sakumoto M, Yoshida A, Setsu N, Kobayashi E, Kawai A, Kondo T
  • Journal Title: Tiss Cult Res Commun Volume: 36 Pages: 41-48
  • NAID: 130007472998
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of cell line of undifferentiated pleomorphic sarcoma (2017)
  • Author(s): Takai Y, Oyama R, Kito F, Sakumoto M, Shiozawa K, Qiao Z, Nakajima K, Takahashi M, Yoshida A, Setsu N, Kobayashi E, Kawai A, Kondo T
  • Journal Title: Tiss Cult Res Commun Volume: 36 Pages: 41-48
  • NAID: 130006250568
  • Peer Reviewed / Open Access
• [Journal Article] Proteomic approach toward determining the molecular background of pazopanib resistance in synovial sarcoma (2017)
  • Author(s): Qiao Zhiwei、Shiozawa Kumiko、Kondo Tadashi
  • Journal Title: Oncotarget Volume: 8 Issue: 65 Pages: 109587-109595
  • DOI: 10.18632/oncotarget.22730
  • Peer Reviewed / Open Access
• [Journal Article] Meta-analysis identifies endothelin-3 as a prognostic biomarker in gastrointestinal stromal tumors (2017)
  • Author(s): Qiao Z, Kito F, Kondo T
  • Journal Title: J Sarcoma Res Volume: 1 Pages: 1001-1005
  • Peer Reviewed / Open Access
• [Journal Article] Metastasis-associated gene signature in primary myxoid liposarcoma identified through a gene expression study (2017)
  • Author(s): Qiao Z, Tajim T, Kito F, Arai Y, Kawai A, Kondo T
  • Journal Title: J Electrophoresis Volume: 61 Pages: 9-15
  • NAID: 130006039435
  • Peer Reviewed / Open Access
• [Journal Article] Secretomics identifies follistatin as a predictive biomarker for response to treatment with tyrosine kinase inhibitors in synovial sarcoma (2017)
  • Author(s): Qiao Z, Kito F, Takai Y, Oyama R, Kondo T
  • Journal Title: J Electrophoresis Volume: 61 Pages: 1-7
  • NAID: 130006039437
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and proteomic characterization of NCC-LMS1-C1, a novel cell line of primary leiomyosarcoma of the bone (2017)
  • Author(s): Sakumoto Marimu、Takahashi Mami、Oyama Rieko、Takai Yoko、Kito Fusako、Shiozawa Kumiko、Qiao Zhiwei、Yoshida Akihiko、Endo Makoto、Kawai Akira、Kondo Tadashi
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 47 Issue: 10 Pages: 954-961
  • DOI: 10.1093/jjco/hyx096
  • Peer Reviewed / Open Access
• [Journal Article] Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is a novel biomarker of myxofibrosarcoma invasion identified by global protein expression profiling (2017)
  • Author(s): Kikuta Kazutaka、Kubota Daisuke、Yoshida Akihiko、Qiao Zhiwei、Morioka Hideo、Nakamura Masaya、Matsumoto Morio、Chuman Hirokazu、Kawai Akira、Kondo Tadashi
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics Volume: 1865 Issue: 9 Pages: 1160-1166
  • DOI: 10.1016/j.bbapap.2017.06.023
  • NAID: 130007498586
  • Peer Reviewed / Open Access
• [Journal Article] Generation of novel patient-derived CIC-DUX4 sarcoma xenografts and cell lines (2017)
  • Author(s): Oyama Rieko、Takahashi Mami、Yoshida Akihiko、Sakumoto Marimu、Takai Yoko、Kito Fusako、Shiozawa Kumiko、Qiao Zhiwei、Arai Yasuhito、Shibata Tatsuhiro、Araki Yoshihiro、Endo Makoto、Kawai Akira、Kondo Tadashi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-017-04967-0
  • Peer Reviewed / Open Access
• [Journal Article] Proteomic study of hepatocellular carcinoma using a novel modified aptamer-based array (SOMAscanTM) platform. (2017)
  • Author(s): Qiao Z, Pan X, Parlayan C, Ojima H, Kondo T.
  • Journal Title: Biochim Biophys Acta. Volume: 4 Issue: 4 Pages: 434-443
  • DOI: 10.1016/j.bbapap.2016.09.011
  • Peer Reviewed / Open Access
• [Journal Article] miR-125b and miR-100 Are Predictive Biomarkers of Response to Induction Chemotherapy in Osteosarcoma. (2016)
  • Author(s): Kubota D, Kosaka N, Fujiwara T, Yoshida A, Arai Y, Qiao Z, Takeshita F, Ochiya T, Kawai A, Kondo T.
  • Journal Title: Sarcoma. Volume: 2016 Pages: 1390571-1390571
  • DOI: 10.1155/2016/1390571
  • Peer Reviewed / Open Access
• [Journal Article] Synovial sarcoma cell lines showed reduced DNA repair activity and sensitivity to a PARP inhibitor. (2016)
  • Author(s): Yamasaki H, Miyamoto M, Yamamoto Y, Kondo T, Watanabe T, Ohta T.
  • Journal Title: Genes Cells. Volume: 21(8) Issue: 8 Pages: 852-860
  • DOI: 10.1111/gtc.12387
  • Peer Reviewed / Open Access
• [Journal Article] Proteogenomics for the Study of Gastrointestinal Stromal Tumors. (2016)
  • Author(s): Kondo T.
  • Journal Title: Adv Exp Med Biol. Volume: 926 Pages: 139-151
  • DOI: 10.1007/978-3-319-42316-6_9
  • ISBN: 9783319423142, 9783319423166
  • Peer Reviewed / Open Access
• [Journal Article] A novel p53 target gene FUCA1 encodes a fucosidase and regulates growth and survival of cancer cells. (2016)
  • Author(s): Ezawa I, Sawai Y, Kawase T, Okabe A, Tsutsumi S, Ichikawa H, Kobayashi Y, Tashiro F, Namiki H, Kondo T, Semba K, Aburatani H, Taya Y, Nakagama H, Ohki R.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 6 Pages: 734-745
  • DOI: 10.1111/cas.12933
  • Peer Reviewed / Open Access
• [Journal Article] Sacral Tuberculosis (2016)
  • Author(s): 0kuyama Y, Baba A, Kobashi Y, Anazawa U
  • Journal Title: Internal Medicine Volume: 55 Issue: 14 Pages: 1939-1940
  • DOI: 10.2169/internalmedicine.55.6500
  • NAID: 130005165009
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Long-term Follow-up of an Osteoid Osteoma of the Femoral Neck Treated with Percutaneous Procedure Under Computed Tomography Guidance (2016)
  • Author(s): Anazawa U, Watanabe I, Mizuno S and Hotta H
  • Journal Title: Chemo Open Access Volume: 5
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology (2016)
  • Author(s): Shibata H, Kato S, Sekine I, Abe K, Araki N, Iguchi H, Izumi T, Inaba Y, Osaka I, Kato S, Kawai A, Kinuya S, Kodaira M, Kobayashi E, Kobayashi T, Sato J, Shinohara N, Takahashi S, Takamatsu Y, Takayama K, Takayama K, Tateishi U, Nagakura H, Hosaka M, Morioka H, Moriya T, Yuasa T, Yurikusa T, Yomiya K, Yoshida M
  • Journal Title: ESMO Open Volume: 1 Issue: 2 Pages: e000037-e000037
  • DOI: 10.1136/esmoopen-2016-000037
  • Peer Reviewed / Open Access
• [Presentation] What we can learn from biomarker study; prior probability, patient-derived cancer model, and proteogenomics (2019)
  • Author(s): Tadashi Kondo
  • Organizer: 19th KHUPO Annual International Proteomics Conference
  • Int'l Joint Research / Invited
• [Presentation] プロテオゲノミクスソフトウェアMutated Nucleotide and Amino-acid sequence Generator(MuNAGe) の開発 (2018)
  • Author(s): 服部恵美・塩澤久美子・近藤格
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 希少がん・肉腫の研究―プロテオーム解析によるバイオマーカーの開発から患者由来がんモデルの樹立までー (2018)
  • Author(s): 近藤格
  • Organizer: 第33回日本整形外科学会基礎学術集会
  • Invited
• [Presentation] Novel proteogenomics software to generate sample-specific database: MuNAGe, Mutated Nucleotides and Amino-acid sequence Generator (2018)
  • Author(s): 近藤格、服部恵美
  • Organizer: International Proteogenome Workshop
  • Int'l Joint Research / Invited
• [Presentation] Rare cancer research (2018)
  • Author(s): Tadashi Kondo
  • Organizer: The 2018 Upper Extremity Tumor Treatment and Hand Surgery Advanced Technique Workshop
  • Invited
• [Presentation] Novel software for Protegenomics; Mutated Nucleotides and Amino-Acids Generator (MuNAGe). (2018)
  • Author(s): Emi Hattori, Tadashi Kondo
  • Organizer: The Connective Tissue Oncology Society 2018 Annual Meeting.
  • Int'l Joint Research
• [Presentation] Mutated Nucleotide and Amino-acid sequence Generator (MuNAGe): novel proteogenomics software to generate sample-specific database. (2018)
  • Author(s): Emi Hattori, Kumiko Shiozawa, Tadashi Kondo.
  • Organizer: 17th Human Proteome Organisation World Congress
  • Int'l Joint Research
• [Presentation] Sarcoma research toward novel clinical application. (2018)
  • Author(s): Tadashi Kondo.
  • Organizer: The 12th NCC International Symposium
  • Int'l Joint Research / Invited
• [Presentation] Rare cancer research. (2018)
  • Author(s): Tadashi Kondo
  • Organizer: The 2018 Upper Extremity Tumor Treatment and Hand Surgery Advanced Technique Workshop.
  • Int'l Joint Research / Invited
• [Presentation] Development and application of patient-derived cancer model (2018)
  • Author(s): 近藤格
  • Organizer: 第1回日本サルコーマ治療研究学会学術集会
• [Presentation] Cancer Proteomics for Clinical Application (2017)
  • Author(s): Tadashi Kondo
  • Organizer: 2017 Upper Extremity Tumor Treatment and Hand Surgery Advance Technique Workshop
  • Int'l Joint Research / Invited
• [Presentation] 希少がん・肉腫の新しい治療法の開発を目指した患者由来がんモデルの構築 (2017)
  • Author(s): 近藤格
  • Organizer: Cell Aggregation Meeting 2017
  • Invited
• [Presentation] Japan Team; Proteogenomics for Sarcoma (2017)
  • Author(s): Tadashi Kondo, Mari Masuda, Tesshi Yamada
  • Organizer: 第3回International Cancer Proteogenomics Consortium代表者会議
  • Int'l Joint Research
• [Presentation] 肉腫の新しい治療法のための患者由来がんモデルの開発 (2017)
  • Author(s): 近藤格
  • Organizer: 第37回日本分子腫瘍マーカー研究会
• [Presentation] 希少がんのプロテオーム解析 (2017)
  • Author(s): 近藤格
  • Organizer: 第68回日本電気泳動学会総会
• [Presentation] Evolving Treatment of Sarcomas ;The role of multi-institutional and international collaboration- (2016)
  • Author(s): Akira Kawai
  • Organizer: 4th Singapore Sarcoma Symposium
  • Place of Presentation: カレッジロード（シンガポール）
  • Year and Date: 2016-11-05
• [Presentation] Recent Advances of Sarcoma Treatment in Japan (2016)
  • Author(s): Akira Kawai
  • Organizer: 60th Korean Orthopaedic Association
  • Place of Presentation: Incheon（韓国）
  • Year and Date: 2016-10-19
  • Int'l Joint Research / Invited
• [Presentation] Biomarker development by cancer proteomics (2016)
  • Author(s): Tadashi Kondo
  • Organizer: 10th Central and Eastern European Proteome Conference
  • Place of Presentation: ブダペスト（ハンガリー）
  • Year and Date: 2016-10-11
  • Int'l Joint Research / Invited
• [Presentation] Sarcoma cell lines: Current status and perspectives (2016)
  • Author(s): Xiaoqing Pan, Akihiko Yoshida, Akira Kawai, Tadashi Kondo
  • Organizer: 第89回日本組織培養学会年会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2016-05-25
• [Presentation] 肉腫のプロテオーム解析 (2016)
  • Author(s): 近藤格
  • Organizer: 第89回日本整形外科学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-05-12
  • Invited
• [Presentation] Cancer proteomics (2016)
  • Author(s): Tadashi Kondo
  • Organizer: 2016 Upper Extremity Tumor Treatment and Hand Surgery Advance Technique Workshop
  • Place of Presentation: 上海（中国）
  • Year and Date: 2016-05-06
  • Invited
• [Presentation] Novel patient-derived xenograft and primary tissue culture cell for pre-clinical study in sarcoma (2016)
  • Author(s): Xiaoqing Pan, Mami Takahashi, Hitoshi Ichikawa, Akihiko Yoshida, Akira Kawai, Toshio Imai, Tadashi Kondo
  • Organizer: Annual Meeting of American Association of Cancer Research
  • Place of Presentation: ニューオーリンズ（米国）
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Proteomics approach to sarcoma research toward clinical application (2016)
  • Author(s): Tadashi Kondo
  • Organizer: Asia Oceania Human Proteome Organization
  • Place of Presentation: 台湾南投県魚池郷(台湾)
  • Int'l Joint Research / Invited
• [Remarks] 希少がん研究分野
  • URL: http://www.nccri.ncc.go.jp/s015/
• [Patent(Industrial Property Rights)] 粘液線維肉腫の浸潤性判定補助方法および当該方法に利用される粘液線維肉腫の浸潤性判定用キット (2017)
  • Inventor(s): 菊田一貴、近藤格、川井章
  • Industrial Property Rights Holder: 国立がん研究センター、シスメックス株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-035001
  • Filing Date: 2017-02-27