Development of the novel ant-metastatuc therapy against circulating tumor cells

• Project/Area Number: 25670661
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses
• Principal Investigator: KAZUYUKI Itoh 地方独立行政法人大阪府立病院機構大阪府立成人病センター(研究所), その他部局等, その他 (20301806)
• Co-Investigator(Renkei-kenkyūsha): YOSHIKAWA Hideki 大阪大学, 医学系研究科, 教授 (60191558)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 転移 / 循環腫瘍細胞 / 骨肉腫 / 血管内皮細胞増殖因子 / 組織の硬さ / 循環がん細胞 / 細胞死

Outline of Final Research Achievements

Circulation tumor cells (CTCs) appeared in the early phase of metastasis and the growth of metastasized cells in the target organs are critical during the multistep lung metastasis by musclo-skeletal malignant tumors. We established the method to purify the living CTCs from osteosarcoma (OS) bearing mouse using our previously reported highly metastatic OS cell line LM8. By comparison between CTCs from LM8 and primary tumor cells, we found the higher anti-anokis activity of LM8-derived CTCs. We also found that vascular endothelial growth factor (VEGF) plays an important role of three dimensional growth of OS in soft-stiffness condition mimicking lung, compare to the hard stiffness primary sites. Using the small molecules targeted to the VEGF signal, we confirmed the effective inhibition of OS lung metastasis in vivo syngeneic mouse orthotropic experimental metastasis model.

Research Products

• [Journal Article] EGF-stimulated AKT activation is mediated by EGFR recycling via an early endocytic pathway in a gefitinib-resistant human lung cancer cell line. (2015)
  • Author(s): Nishimura Y, Takiguchi S, Ito S, Itoh K.
  • Journal Title: International Journal of Oncology Volume: 46 (4) Issue: 4 Pages: 1721-1729
  • DOI: 10.3892/ijo.2015.2871
  • Peer Reviewed / Open Access
• [Journal Article] Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma. (2014)
  • Author(s): Imura Y, Yasui H, Outani H, Wakamatsu T, Hamada K, Nakai T, Yamada S, Myoui A, Araki N, Ueda T, Itoh K, Yoshikawa H, Naka N.
  • Journal Title: Mol Cancer Volume: 13 Issue: 1 Pages: 185-185
  • DOI: 10.1186/1476-4598-13-185
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Deflection of VEGF action by SS18-SSX and composite VEGF- and CXCR4-targeted therapy in synovial sarcoma. (2014)
  • Author(s): Wakamatsu T, Naka N, Sasagawa S, Tanaka T, Takenaka S, Araki N, Ueda T, Nishizawa Y, Yoshikawa H, Itoh K.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 9 Pages: 1124-1134
  • DOI: 10.1111/cas.12469
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS. (2014)
  • Author(s): Outani H, Tanaka T, Wakamatsu T, Imura Y, Hamada K, Araki N, Itoh K, Yoshikawa H, Naka N.
  • Journal Title: BMC Cancer Volume: 14 Issue: 1 Pages: 455-455
  • DOI: 10.1186/1471-2407-14-455
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tailored therapeutic strategies for synovial sarcoma : Receptor tyrosine kinase pathway analyses predict sensitivity to the mTOR inhibitor RAD001 (2014)
  • Author(s): Yasui, H., Naka, N., Imura, Y., Outani, H., Kaneko, K., Hamada, KI., Sasagawa, S., Araki, N., Ueda, T., Itoh, K., Myoui, A., and Yoshikawa, H
  • Journal Title: Cancer Lett Volume: 347(1) Issue: 1 Pages: 114-122
  • DOI: 10.1016/j.canlet.2014.01.027
  • Peer Reviewed
• [Presentation] 類上皮肉腫に対するmTORとc-METを標的とした抗腫瘍効果 (2014)
  • Author(s): 伊村慶紀、王谷英達、濱田健一郎、名井陽、荒木信人、上田孝文、伊藤和幸、吉川秀樹、中紀文
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 骨軟部肉腫の転移ドライバの同定と発現制御および分子標的としての可能性の検討 (2014)
  • Author(s): 笹川覚、伊藤和幸
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 肺癌細胞内におけるEGF刺激によるAKT活性化はEGFR再循環により促進される (2014)
  • Author(s): 西村行生、瀧口総一、伊藤和幸
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25
• [Presentation] 滑膜肉腫へのmTOR阻害剤の効果を予測するバイオメーカーの提案 (2014)
  • Author(s): 安井広彦、中紀文、井村慶紀、王谷英達、金子恵子、濱田健一郎、荒木信人、上田孝文、伊藤和幸、名井陽、吉川秀樹
  • Organizer: 第47回日本整形外科学会 骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17 – 2014-07-18
• [Presentation] 類上皮肉腫に対するmTOR阻害剤( RAD001)とMET阻害剤(INC280)の併用による抗腫瘍効果 (2014)
  • Author(s): 井村慶紀、中紀文、安井広彦、王谷英達、濱田健一郎、名井陽、荒木信人、上田孝文、伊藤和幸、吉川秀樹
  • Organizer: 第47回日本整形外科学会 骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17 – 2014-07-18
• [Presentation] 骨・軟部腫瘍の転移Driverの同定と転移抑制のための分子標的探索 (2014)
  • Author(s): 笹川覚、伊藤和幸
  • Organizer: 第47回日本整形外科学会 骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17 – 2014-07-18
• [Presentation] 肉腫の転移と分子標的治療 (2014)
  • Author(s): 伊藤和幸
  • Organizer: 第47回日本整形外科学会 骨・軟部腫瘍学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-17 – 2014-07-18
  • Invited
• [Presentation] 肺癌細胞内におけるEGFRシグナル下流のAKT活性化はEGFR再循環により促進される (2014)
  • Author(s): 西村行生、瀧口総一、伊藤和幸
  • Organizer: 第23回日本がん転移学会学術集会・総会
  • Place of Presentation: 金沢市文化ホール・金沢ニューグランドホテル（石川県金沢市）
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] 骨転移の病態と最新治療 (2014)
  • Author(s): 伊藤和幸
  • Organizer: 第23回日本がん転移学会学術集会・総会
  • Place of Presentation: 金沢市文化ホール・金沢ニューグランドホテル（石川県金沢市）
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] Dynamic analysis of lung metastasis by mouse osteosarcoma. (2014)
  • Author(s): Tanaka T, Yui Y, Naka N, Wakamatsu T, Yoshikawa H, Itoh K.
  • Organizer: 15th International Biennial Congress of the Metastasis Research Society
  • Place of Presentation: The German Cancer Research Centre, Heidelberg, Germany
  • Year and Date: 2014-06-28 – 2014-07-01
• [Presentation] Sodium butyrate induced cellular senescence, inhibited invasion and modulated sellular metabolism in glioblastoma cells (2014)
  • Author(s): Nakagawa H, Shindou M, Sasagawa S, Itoh K.
  • Organizer: American Association for Cancer Research Annual Meeting 2014
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] 転移の病態とがんの不均一性 (2013)
  • Author(s): 伊藤和幸
  • Organizer: 第２２回日本がん転移学会学術集会・総会
  • Place of Presentation: ホテルブエナビスタ（長野県松本市）
  • Invited
• [Presentation] 骨軟部腫瘍におけるTwist1の発現と機能解析 (2013)
  • Author(s): 笹川覚、伊藤和幸
  • Organizer: 第２２回日本がん転移学会学術集会・総会
  • Place of Presentation: ホテルブエナビスタ（長野県松本市）
• [Presentation] 滑膜肉腫におけるCXCL12/CXCR4分子標的治療 (2013)
  • Author(s): 若松透、中紀文、田中太晶、竹中聡、笹川覚、吉岡潔子、荒木信人、上田孝文、吉川秀樹、伊藤和幸
  • Organizer: 第４６回日本整形外科学会 骨・軟部腫瘍学術集会
  • Place of Presentation: 東京ドームホテル（東京都）
• [Presentation] Sarcomaの転移におけるTwist1の発現制御と機能的役割の解析 (2013)
  • Author(s): 笹川覚、伊藤和幸
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市神奈川県）
• [Presentation] 滑膜肉腫の３次元増殖におけるVEGF、CXCR4シグナルの重要性および分子標的としての可能性 (2013)
  • Author(s): 若松透、中紀文、笹川覚、田中太晶、竹中聡、荒木信人、上田孝文、吉岡潔子、西澤恭子、吉川秀樹、伊藤和幸
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市神奈川県）
• [Presentation] Investigationg the functional role and expression control of Twist1 in sarcoma (2013)
  • Author(s): Sasagawa, S., and Itoh, K.
  • Organizer: The 18th Annual Meeting of the Connective Tissue Oncology Society
  • Place of Presentation: Sheraton New York Times Square Hotel (New York, NY, USA)
• [Presentation] VEGF signal axis is a potential therapeutic molecular target for synovial sarcoma (2013)
  • Author(s): Wakamatsu, T., Naka, N., Sasagawa, S., Tanaka, T., Takenaka, S., Araki, N., Ueda, T., Yoshioka, K., Nishizawa, Y., Yoshikawa, H., and Itoh, K.
  • Organizer: The 18th Annual Meeting of the Connective Tissue Oncology Society
  • Place of Presentation: Sheraton New York Times Square Hotel (New York, NY, USA)
• [Remarks] 大阪府立成人病センター 研究所 生物学部門
  • URL: http://www.mc.pref.osaka.jp/laboratory/department/seibutsu/
• [Remarks] 大阪府立成人病センター 研究所 生物学部門
  • URL: http://www.mc.pref.osaka.jp/omc2/category/biology.html