Investigation of the roles of tumor environment in osteosarcoma

• Project/Area Number: 22700887
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: Keio University
• Principal Investigator: SHIMIZU Takatsune 慶應義塾大学, 医学部, 特任助教 (40407101)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 癌 / 環境 / 腫瘍 / 微小環境

Research Abstract

The roles of environmental soluble factors in the formation of histopathological characteristics of osteosarcoma(OS) remains to be elucidated. Here, a newly established murine OS model was used to clarify the roles of environmental factors such as fibroblast growth factor-2(Fgf2) or leukemia inhibitory factor(Lif) in the maintenance of OS cells in an immature state. These factors were highly expressed in stromal fibroblasts and macrophages, but not in OS cells, and potently suppressed osteogenesis of OS cells in vitro and in vivo. Further investigations revealed that the activation of Erk1/2 induced by these factors was deeply involved in the process of OS differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of OS cells and modulated the sensitivity to an anti-cancer drug. These findings suggest that the seemingly chaotic structures of OS could be dependent on the distribution of such factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of OS.

Research Products

• [Journal Article] Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma (2012)
  • Author(s): Shimizu T, Ishikawa T, Iwai S, Ueki A, Sugihara E, Onishi N, Kuninaka S, Miyamoto T, Toyama Y, Ijiri H, Mori H, Matsuzaki Y, Yaguchi T, Nishio H, Kawakami Y, Ikeda Y, Saya H
  • Journal Title: Mol. Cancer Res. Volume: 10 Pages: 454-468
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor-2 (Fgf2) is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma (2012)
  • Author(s): Shimizu T, et al
  • Journal Title: Molecular Cancer Research Volume: 10 Pages: 454-468
  • Peer Reviewed
• [Journal Article] Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12 (2011)
  • Author(s): Kobayashi Y, Shimizu T, Naoe H, Ueki A, Ishizawa J, Chiyoda T, Onishi N, Sugihara E, Nagano O, Banno K, Kuninaka S, Aoki D, Saya H
  • Journal Title: Am. J. Pathol Volume: 179 Pages: 1471-82
  • Peer Reviewed
• [Journal Article] Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor (2011)
  • Author(s): Sugihara E, Shimizu T, et al
  • Journal Title: Oncogene Volume: (In press)
  • Peer Reviewed
• [Journal Article] Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12 (2011)
  • Author(s): Kobayashi Y, Shimizu T, et al
  • Journal Title: American Journal of Pathology Volume: 179 Pages: 1471-1482
  • Peer Reviewed
• [Journal Article] c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis (2010)
  • Author(s): Shimizu T, Ishikawa T, Sugihara E, Kuninaka S, Miyamoto T, Mabuchi Y, Matsuzaki Y, Tsunoda T, Miya F, Morioka H, Nakayama R, Kobayashi E, Toyama Y, Kawai A, Ichikawa H, Hasegawa T, Okada S, Ito T, Ikeda Y, Suda T, Saya H
  • Journal Title: Oncogene Volume: 29 Pages: 5687-99
  • Peer Reviewed
• [Journal Article] c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis (2010)
  • Author(s): Takatsune Shimizu, et al.
  • Journal Title: Oncogene Volume: 29 Pages: 5687-5699
  • Peer Reviewed
• [Presentation] Multifunctional roles of Fibroblast growth factor-2(Fgf2) in the histopathology of murine osteosarcoma (2011)
  • Author(s): 清水孝恒
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Multifunctional roles of Fibroblast growth factor-2 (Fgf2) in the histopat hology of murine osteosarcoma (2011)
  • Author(s): 清水孝恒
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-04
• [Presentation] Mesenchymal differentiation potentials modified osteosarcoma stem cell activities (2010)
  • Author(s): 清水孝恒
  • Organizer: 第101回アメリカ癌学会
  • Place of Presentation: Walter E.ワシントンコンベンションセンター
  • Year and Date: 2010-04-22
• [Presentation] Mesenchymal differentiation potentials modify osteosarcoma stem cell activities (2010)
  • Author(s): 清水孝恒
  • Organizer: American Association for cancer research 101^<st> Annual meeting 2010
  • Place of Presentation: Washington, U. S. A.
  • Year and Date: 2010-04-21
• [Book] がん幹細胞研究の動向と治療標的としての将来性.最新医学(特集:がん幹細胞と支持細胞を標的とする薬剤の開発) (2011)
  • Author(s): 清水孝恒, 吉田剛, 佐谷秀行
• [Book] 最新医学 (2011)
  • Author(s): 清水孝恒、吉田剛、佐谷秀行
  • Total Pages: 6
  • Publisher: 最新医学社
• [Remarks]
  • URL: http://www.genereg.jp/
• [Remarks]
  • URL: http://www.genereg.jp/