Investigation and conquest of the therapeutic resistant dormancy in osteosarcoma mediated by insulin-like growth factor (IGF) signaling

• Project/Area Number: 24501320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Hoshi University
• Principal Investigator: SHIMIZU TAKATSUNE 星薬科大学, 薬学部, 准教授 (40407101)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 骨肉腫 / 癌微小環境 / 治療抵抗性 / osteosarcoma / dormancy / drug resistance / autophagy

Outline of Final Research Achievements

Osteosarcoma (OS) is a malignant tumor for which new approaches to overcome therapy resistance are urgently required. On the basis of the identification of IGF2 as a soluble factor whose expression is elevated in tumors after chemotherapy, we have examined the role of this factor. Continuous exposure of OS cells to IGF2 promoted cell survival in a state of dormancy that conferred marked resistance to chemotherapeutic drugs. Dormancy mediated by IGF2 was associated with down-regulation of IGF signaling pathway. Screening of various agents revealed that such dormancy was dependent on an enhanced autophagy and the presence of extracellular glutamine. Inhibition of autophagy or depletion of glutamine increased the efficacy of chemotherapy in mice bearing OS tumors. Our results suggest that activation of IGF signaling in regions of a tumor that become separated from the vasculature allows the survival of stressed tumor cells that are subsequently responsible for minimal residual disease.

Research Products

• [Journal Article] IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress (2014)
  • Author(s): Shimizu T, Sugihara E, Yamaguchi-Iwai S, Tamaki S, Koyama Y, Kamel W, Ueki A, Ishikawa T, Chiyoda T, Osuka S, Onishi N, Ikeda H, Kamei J, Matsuo K, Fukuchi Y, Nagai T, Toguchida J, Toyama Y, Muto A, Saya H
  • Journal Title: Cancer Res Volume: 74 Issue: 22 Pages: 6531-6541
  • DOI: 10.1158/0008-5472.can-14-0914
  • Peer Reviewed
• [Journal Article] Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation. (2014)
  • Author(s): Nobusue H
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 3368-3368
  • DOI: 10.1038/ncomms4368
  • Peer Reviewed
• [Journal Article] Glycan profiling of gestational choriocarcinoma using a lectin microarray (2014)
  • Author(s): Kobayashi Y, Masuda K, Banno K, Kobayashi N, Umene K, Nogami Y, Tsuji K, Ueki A, Nomura H, Sato K, Tominaga E, Shimizu T, Saya H, Aoki D
  • Journal Title: Oncology Reports Volume: 31 Issue: 3 Pages: 1121-1131
  • DOI: 10.3892/or.2014.2979
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state. (2013)
  • Author(s): Mori T
  • Journal Title: Oncogene Volume: Epub ahead of print Issue: 33 Pages: 4236-4241
  • DOI: 10.1038/onc.2013.545
  • Peer Reviewed
• [Journal Article] IGF1 receptor signaling regulates adaptive radioprotection in glioma stemcells (2013)
  • Author(s): Osuka S. Sampetrean O, Shimizu T, Saga l, Onishi N, Sugihara E, Okubo J, Fujita S, Takano S, Matsumura A, Saya H
  • Journal Title: Stem Cells Volume: 31 Issue: 4 Pages: 627-640
  • DOI: 10.1002/stem.1328
  • Peer Reviewed
• [Journal Article] Twist2 functions as a tumor suppressor in murine osteosarcoma cells. (2013)
  • Author(s): Ishikawa T, Shimizu T, Ueki A, Yamaguchi S, Onishi N, Sugihara E, Kuninaka S, Miyamoto T, Morioka H, Nakayama R, Kobayashi E, Toyama Y, Mabuchi Y, Matsuzaki Y, Yamaguchi R, Miyano S and Saya H
  • Journal Title: Cancer Sci Volume: (in press) Issue: 7 Pages: 880-888
  • DOI: 10.1111/cas.12163
  • Peer Reviewed
• [Journal Article] LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression (2012)
  • Author(s): Chiyoda, T.
  • Journal Title: J Cell Biol Volume: 197 Issue: 5 Pages: 625-41
  • DOI: 10.1083/jcb.201110110
  • Peer Reviewed
• [Journal Article] Up-regulation of imp3 confers in vivo tumorigenicity on murine osteosarcoma cells. (2012)
  • Author(s): Ueki A, Shimizu T, Masuda K, Yamaguchi SI, Ishikawa T, Sugihara E, Onishi N, Kuninaka S, Miyoshi K, Muto A, Toyama Y, Banno K, Aoki D, Saya H.
  • Journal Title: PLoS One Volume: 7(11) Issue: 11 Pages: e50621-e50621
  • DOI: 10.1371/journal.pone.0050621
  • Peer Reviewed
• [Presentation] マウス骨肉腫幹細胞の同定と克服への挑戦 (2014)
  • Author(s): 清水孝恒、武藤章弘、佐谷秀行
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] インスリン様増殖因子シグナルは骨肉腫細胞に治療抵抗性休眠状態を誘導する (2014)
  • Author(s): 清水孝恒
  • Organizer: 第2回がんと代謝研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
  • Invited
• [Presentation] インスリンシグナルによる骨肉腫休眠状態は微小残存病変につながる (2013)
  • Author(s): 清水孝恒、石川智樹、山口さやか、杉原英志、植木有紗、大西伸幸、國仲慎治、武藤章弘、安積彩香、大久保智啓、佐谷秀行
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Characterization and conquest of mouse osteosarcoma stem cells (2013)
  • Author(s): Takatsune Shimizu, Akihiro Muto, Hideyuki Saya
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Molecular mechanism of in vivo tumorigenesis
  • Author(s): Takatsune Shimizu
  • Organizer: The 11th Korea-Japan-Germany Joint Symposium on Cancer and Aging
  • Place of Presentation: Gyeongju, Korea
• [Presentation] マウス骨肉腫幹細胞の樹立とその特徴
  • Author(s): 清水孝恒、佐谷秀行
  • Organizer: 第１０回日本臨床腫瘍学会学術集会
  • Place of Presentation: 大阪
  • Invited
• [Book] 実験医学増刊号 がん微小環境と標的治療 (2015)
  • Author(s): 清水孝恒
  • Total Pages: 207
  • Publisher: 羊土社
• [Book] モデル動物利用マニュアル 疾患モデルの作成と利用 がん (2012)
  • Author(s): 清水孝恒、佐谷秀行
  • Total Pages: 633
  • Publisher: LIFE-SCIENCE INFORMATION CENTER
• [Remarks] 星薬科大学・薬学部・病態生理学教室
  • URL: http://www.hoshi.ac.jp/home/kyoiku/kyoushitsuhgaid/15kyoushitsu.byoutai.html
• [Remarks] 慶應義塾大学医学部・先端医科学研究所・遺伝子制御研究部門
  • URL: http://www.genereg.jp/
• [Remarks] 星薬科大学・薬学部・病態生理学教室・清水孝恒
  • URL: http://www.hoshi.ac.jp/home/kyoiku/KyoinJiseki/t-shimizu.pdf