New direction for the conquest of the EMT-related peritoneum dissemination in chemoresistant ovarian cancer

• Project/Area Number: 25670701
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Nagoya University
• Principal Investigator: HIROAKI KAJIYAMA 名古屋大学, 医学(系)研究科(研究院), 准教授 (00345886)
• Co-Investigator(Renkei-kenkyūsha): SENGA Takeshi 名古屋大学, 大学医学系研究科, 准教授 (80419431)
• 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: 卵巣癌 / 腹膜播種 / マイクロRNA / TGF-β / 腹膜中皮細胞 / 薬剤耐性 / 腹腔内微小環境 / 細胞コミュニケーション / microRNA

Outline of Final Research Achievements

Mesothelial cells (MC) are the primary components of the tumor microenvironment for ovarian cancer (OC) cells. We show that TGF-beta-stimulated human MC (Cancer-associated mesothelial cells: CAM) are able to promote cancer cell attachment and proliferation and the activation of the promoter activities of MMP-2 and MMP-9, which are metalloproteinases necessary for tumor invasion. Expression of the miR-200 family was down-regulated in CAM, and restoration of the expression of miR-200 family members in MC suppressed cancer cell attachment and proliferation. Down-regulation of the miR-200 family by TGF-beta-induced Fibronectin production, which promoted cancer cell attachment to CAM. Finally, we demonstrated that the delivery of the miR-200s to CAM in mice inhibited OC cell implantation and dissemination. Our results suggest that alteration of the tumor microenvironment by the miR-200 family could be a novel therapeutic strategy for OC treatment.

Research Products

• [Journal Article] HOXB13 and ALX4 induce SLUG expression for the promotion of EMT and cell invasion in ovarian cancer cells (2015)
  • Author(s): 1.Yuan H, Kajiyama H, Ito S, Chen D, Shibata K, Hamaguchi M, Kikkawa F, Senga T
  • Journal Title: Oncotarget Volume: in press
  • Peer Reviewed
• [Journal Article] GPC3 expression in mouse ovarian cancer induces GPC-specific T cell-mediated immune response through M1 macrophages and suppresses tumor growth. (2014)
  • Author(s): Luo C, Shibata K, Suzuki S, Kajiyama H, Senga T, Koya Y, Daimon M, Yamashita M, Kikkawa F.
  • Journal Title: Oncol Rep. Volume: 32 Issue: 3 Pages: 913-21
  • DOI: 10.3892/or.2014.3300
  • Peer Reviewed / Open Access
• [Journal Article] Expression of the miR200 Family of microRNAs in Mesothelial Cells Suppresses the Dissemination of Ovarian Cancer Cells. (2014)
  • Author(s): Sugiyama K, Kajiyama H, Shibata K, Yuan H, Kikkawa F, Senga T.
  • Journal Title: Mol Cancer Ther. Volume: 13 Issue: 8 Pages: 2081-91
  • DOI: 10.1158/1535-7163.mct-14-0135
  • Peer Reviewed
• [Journal Article] PLAGL2 regulates actin cytoskeletal architecture and cell migration. (2014)
  • Author(s): Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K, Hamaguchi M, Kikkawa F, Kajiyama H, Senga T.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 9 Pages: 1993-2001
  • DOI: 10.1093/carcin/bgu081
  • Peer Reviewed
• [Journal Article] PLAGL2 regulates actin cytoskeletalarchitecture and cell migration. (2014)
  • Author(s): Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K,Hamaguchi M, Kikkawa F, Kajiyama H, Senga T
  • Journal Title: Carcinogenesis Volume: in press
  • Peer Reviewed
• [Journal Article] Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells. (2014)
  • Author(s): Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M.
  • Journal Title: Cancer Sci. Volume: in press
  • Peer Reviewed
• [Journal Article] Is there any association between where patients spend the end of life and survival after anticancer treatment for gynecologic malignancy? (2014)
  • Author(s): Kajiyama H, Utsumi F, Higashi M, Sakata J, Sekiya R, Mizuno M, Umezu T, Suzuki S, Yamamoto E, Mitsui H, Niimi K, Shibata K, Kikkawa F.
  • Journal Title: J Palliat Med. Volume: 17 Issue: 3 Pages: 325-30
  • DOI: 10.1089/jpm.2013.0366
  • Peer Reviewed
• [Journal Article] Recurrence-predicting prognostic factors for patients with early-stage epithelial ovarian cancer undergoing fertility-sparing surgery: a multi-institutional study. (2014)
  • Author(s): Kajiyama H, Mizuno M, Shibata K, Yamamoto E, Kawai M, Nagasaka T, Kikkawa F.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. Volume: 175 Pages: 97-102
  • DOI: 10.1016/j.ejogrb.2014.01.014
  • Peer Reviewed
• [Journal Article] Survival benefit of taxane plus platinum in recurrent ovarian cancer with non-clear cell, non-mucinous histology. (2014)
  • Author(s): Kajiyama H, Shibata K, Mizuno M, Umezu T, Suzuki S, Sekiya R, Niimi K, Mitsui H, Yamamoto E, Kawai M, Nagasaka T, Kikkawa F.
  • Journal Title: J Gynecol Oncol. Volume: 25 Issue: 1 Pages: 43-50
  • DOI: 10.3802/jgo.2014.25.1.43
  • Peer Reviewed
• [Journal Article] Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation. (2014)
  • Author(s): Shinjo K, Yamashita Y, Yamamoto E, Akatsuka S, Uno N, Kamiya A, Niimi K, Sakaguchi Y, Nagasaka T, Takahashi T, Shibata K, Kajiyama H, Kikkawa F, Toyokuni S.
  • Journal Title: Int J Cancer Volume: in press
  • Peer Reviewed
• [Journal Article] ALX1 induces snail expression to promote epithelial-to-mesenchymal transition and invasion of ovarian cancer cells. (2013)
  • Author(s): Yuan H, Kajiyama H, Ito S, Yoshikawa N, Hyodo, Shibata K,Hamaguch M, Kikkawa F, Senga T.
  • Journal Title: Cancer Res Volume: 73(5) Issue: 5 Pages: 1581-1590
  • DOI: 10.1158/0008-5472.can-12-2377
  • Peer Reviewed
• [Journal Article] Effect of Indirect Nonequilibrium Atmospheric Pressure Plasma on Anti-Proliferative Activity against Chronic Chemo-Resistant Ovarian Cancer Cells In Vitro and In Vivo (2013)
  • Author(s): Fumi Utsumi, Hiroaki Kajiyama, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Hiroki Kondo, Hiroyuki Kano, Masaru Hori, and Fumitaka Kikkawa
  • Journal Title: PLoS ONE Volume: 8 Issue: 12 Pages: e81576-e81576
  • DOI: 10.1371/journal.pone.0081576
  • Peer Reviewed
• [Presentation] PLAGL2 regulates cell migration and actin cytoskeleton organization (2014)
  • Author(s): 関谷龍一郎、三井寛子、鈴木史朗、水野美香、柴田清住、梶山広明、千賀威、吉川史隆
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 神奈川県横浜市 パシフィコ横浜
  • Year and Date: 2014-10-27
• [Presentation] 薬剤耐性卵巣癌におけるEMT転写因子ZEB1および誘導因子TGF-βの関与 (2014)
  • Author(s): 坂田 純、梶山広明、関谷龍一郎、三井寛子、鈴木史朗、梅津朋和、水野美香、柴田清住、吉川史隆
  • Organizer: 第56回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 栃木県宇都宮市 栃木県総合文化センター
  • Year and Date: 2014-07-17
• [Presentation] Future Perspective of Strategic Plasma Therapy for Refractory Epithelial Ovarian Cancer (2014)
  • Author(s): Hiroaki Kajiyama, Fumi Utsumi, Kae Nakamura, Hiromasa Tanaka , Masaru Hori , Fumitaka Kikkawa
  • Organizer: The 1st International Workshop on Plasma for Cancer Treatment
  • Place of Presentation: Washington DC, USA
  • Invited
• [Presentation] 薬剤耐性獲得卵巣癌細胞におけるEMT誘導性とそのメカニズム (2013)
  • Author(s): 梶山広明
  • Organizer: 第54回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 東京都港区 ホテル グランパシフィック ＬＥ ＤＡＩＢＡ
• [Presentation] 脈管侵襲陽性例における上皮間葉転換誘導転写因子Twistの発現意義 ～子宮頸癌症例の生存分析から～ (2013)
  • Author(s): 梶山広明
  • Organizer: 第54回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 東京都港区 ホテル グランパシフィック ＬＥ ＤＡＩＢＡ
• [Presentation] Perspective of strategic plasma therapy for prognostic improvement of patients with ovarian cancer (2013)
  • Author(s): Hiroaki Kajiyama, Fumi Utsumi, Kae Nakamura, Hiromasa Tanaka , Masaru Hori , Fumitaka Kikkawa
  • Organizer: 2013 JSAP-MRS Joint Symposia
  • Place of Presentation: Kyoto Doshisya University
  • Invited
• [Presentation] Perspective of fertility-sparing surgery in patients with early-stage epithelial ovarian cancer (2013)
  • Author(s): Hiroaki Kajiyama
  • Organizer: Annual Symposium of KSGO and KGOG
  • Place of Presentation: Seoul, Korea
  • Invited
• [Book] EBM婦人科疾患の治療 2013-2014 (2013)
  • Author(s): 梶山広明
  • Total Pages: 522
  • Publisher: 南江堂
• [Book] 産科婦人科疾患最新治療 2013-2015 (2013)
  • Author(s): 梶山広明
  • Total Pages: 308
  • Publisher: 中外医学社
• [Book] がん・生殖医療 妊孕性温存の診療 (2013)
  • Author(s): 梶山広明
  • Total Pages: 312
  • Publisher: 医歯薬出版株式会社
• [Remarks] 名古屋大学産婦人科
  • URL: http://www.med.nagoya-u.ac.jp/obgy/
• [Remarks] 名古屋大学産婦人科
  • URL: http://www.med.nagoya-u.ac.jp/obgy/