Analysis of signaling pathways in peritoneal dissemination of ovarian cancer, which leads to investigation for their suppressor reagents.

• Project/Area Number: 19390426
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kyoto University
• Principal Investigator: KONISHI Ikuo Kyoto University, 医学研究科, 教授 (90192062)
• Co-Investigator(Kenkyū-buntansha): MANDAI Masaki 京都大学, 医学研究科, 講師 (80283597) ; MATSUMURA Noriomi 京都大学, 医学研究科, 助教 (20452336) ; BABA Tsukasa 京都大学, 医学研究科, 助教 (60508240) ; ITO Kazuko 信州大学, 医学部・附属病院, 講師 (40303458) ; HORIUCHI Akiko 信州大学, 医学部, 助教 (80334895) ; OSADA Ryosuke 信州大学, 医学部・附属病院, 助教 (80418722) ; OHIRA Satoshi 信州大学, 医学部・附属病院, 助教 (90397315)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2008: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2007: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: 卵巣癌 / 播種性転移 / エピジェネティックス / シグナル伝達 / マイクロアレイ / 低分子化合物 / メチル化 / TGFβ / S100A4 / Snail / RhoA / E-cadherin / Hedgehog

Research Abstract

卵巣癌の微小環境によるシグナル分子のエピジェネティックな変化に伴い、HIF-SNAIL-E-cadherin 経路、S100A4-RhoA 経路、Hedgehog 経路、さらにTGFβ経路の活性化が、卵巣癌細胞の播種性転移を促進させることを明らかとした。さらにRhoA、Hedgehog、TGFβの各シグナル経路を阻害する低分子化合物は、卵巣癌播種性転移の治療薬となりうることを明らかにした。

Research Products

• [Journal Article] Up-regulation of Nuclear Receptor Corepressor (NCoR) in Progestin-induced Growth Suppression of Endometrial Hyperplasia and Carcinoma (2009)
  • Author(s): Kashima H, Horiuchi A, Uchikawa J, Miyamoto T, Suzuki A, Ashida T, Konishi I, Shiozawa T.
  • Journal Title: Anticancer Res 29 Pages: 1023-9
  • Peer Reviewed
• [Journal Article] Lactoferrin is associated with a decrease in oocyte depletion in mice receiving cyclophosphamide (2009)
  • Author(s): Horiuchi Y, Higuchi T, Tatsumi K, Takakura K, Fujii S, Konishi I.
  • Journal Title: Fertil Steril. 91 Pages: 2069-2078
  • Peer Reviewed
• [Journal Article] Phase I study of combination chemotherapy with irinotecan hydrochloride and nedaplatin for cervical squamous cell carcinoma: Japanese gynecologic oncology group study (2009)
  • Author(s): Yamamoto K, Kokawa K, Umesaki N, Nishimura R, Hasegawa K, Konishi I, Saji F, Nishida M, Noguchi H, Takizawa K
  • Journal Title: Oncol Rep 21 Pages: 1005-9
  • Peer Reviewed
• [Journal Article] Human amniotic mesenchymal cells differentiate into chondrocytes (2009)
  • Author(s): Wei JP, Nawata M, Wakitani S, Kametani K, Ota M, Toda A, Konishi I, Ebara S, Nikaido T.
  • Journal Title: Cloning Stem Cells 11 Pages: 19-26
  • Peer Reviewed
• [Journal Article] Feasibility study of neoadjuvant chemotherapy followed by interval debulking surgery for stage III/IV ovarian, tubal, and peritoneal cancers: Japan Clinica lOncology Group Study JCOG0206 (2009)
  • Author(s): Onda T, Kobayashi H, Nakanishi T, Hatae M, Iwasaka T, Konishi I, Shibata T, Fukuda H, Kamura T, Yoshikawa H.
  • Journal Title: Gynecol Oncol 113 Pages: 57-62
  • Peer Reviewed
• [Journal Article] Stress affects uterine receptivity through an ovarianindependent pathway (2009)
  • Author(s): Kondoh E, Okamoto T, Higuchi T, Tatsumi K, Baba T, Murphy SK, Takakura K, Konishi I, Fujii S.
  • Journal Title: Hum Reprod 24 Pages: 945-53
  • Peer Reviewed
• [Journal Article] Alpha 1 antitrypsin activity is decreased in human amnion in premature rupture of the fetal membranes (2009)
  • Author(s): Izumi-Yoneda N, Toda A, Okabe M, Koike C, Takashima S, Yoshida T, Konishi I, Saito S, Nikaido T.
  • Journal Title: Mol Hum Reprod 15 Pages: 49-57
  • Peer Reviewed
• [Journal Article] Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression (2009)
  • Author(s): Liu M, Matsumura N, Mandai M, Li K, Yagi H, Baba T, Suzuki A, Hamanishi J, Fukuhara K, Konishi I.
  • Journal Title: Mod Pathol 22 Pages: 373-84
  • Peer Reviewed
• [Journal Article] Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells : involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E (2009)
  • Author(s): Kashima H, Shiozawa T, Miyamoto T, Suzuki A, Uchikawa J, Kurai M, Konishi I.
  • Journal Title: E. Endocr Relat Cancer. 16 Pages: 113-22
  • Peer Reviewed
• [Journal Article] Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells (2009)
  • Author(s): Baba T, Convery PA, Matsumura N, Whitaker RS, Kondoh E, Perry T, Huang Z, Bentley RC, Mori S, Fujii S, Marks JR, Berchuck A, Murphy SK.
  • Journal Title: Oncogene. 28 Pages: 209-18
  • Peer Reviewed
• [Journal Article] Yin yang 1 modulates taxane response in epithelial ovarian cancer (2009)
  • Author(s): Matsumura N, Huang Z, Baba T, Lee PS, Barnett JC, Mori S, Chang JT, Kuo WL, Gusberg AH, Whitaker RS, Gray JW, Fujii S, Berchuck A, Murphy SK.
  • Journal Title: Mol Cancer Res 7 Pages: 210-20
  • Peer Reviewed
• [Journal Article] Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis (2009)
  • Author(s): Li K, Mandai M, Hamanishi J, Matsumura N, Suzuki A, Yagi H, Yamaguchi K, Baba T, Fujii S, Konishi I.
  • Journal Title: Cancer Immunol Immunother 58 Pages: 641-52
  • Peer Reviewed
• [Journal Article] Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer : high expression of ULBP2 is an indicator of poor prognosis. (2009)
  • Author(s): Li K, Mandai M, Hamanishi J, Matsumura N, Suzuki A, Yagi H, Yamaguchi K, Baba T, Fujii S, Konishi I.
  • Journal Title: Cancer Immunology, Immunotherapy 58 Pages: 641-652
  • Peer Reviewed
• [Journal Article] Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells : involvement of the mitogen-activated protein kinase pathway followed by up-regulation of eyelin D1 and cyclin E. (2009)
  • Author(s): Kashima H, Shiozawa T, Miyamoto T, Suzuki A, Uchikawa J, Kurai M, Konishi I.
  • Journal Title: Endocrine-related cancer 16 Pages: 113-122
  • Peer Reviewed
• [Journal Article] Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression. (2009)
  • Author(s): Liu M, Matsumura N, Mandai M, Li K, Yagi H, Baba T, Suzuki A, Hamanishi J, Fukuhara K, Konishi I.
  • Journal Title: Modern Pathology 22 Pages: 373-384
  • Peer Reviewed
• [Journal Article] Japan Gynecologic Oncology Group.Phase I study of irinotecan combined with mitomycin-C and 5-fluorouracil for gynecological malignancies: the JGOG study (2008)
  • Author(s): Kokawa K, Umesaki N, Yamamoto K, Takizawa K, Konishi I, Hasegawa K
  • Journal Title: Anticancer Res 28 Pages: 2933-9
  • Peer Reviewed
• [Journal Article] Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer (2008)
  • Author(s): Horiuchi A, Kikuchi N, Osada R, Wang C, Hayashi A, Nikaido T, Konishi I
  • Journal Title: Cancer Sci 99 Pages: 2532-9
  • NAID: 10024014761
  • Peer Reviewed
• [Journal Article] I. A new technique using a rubber balloon in emergency second trimester cerclage for fetal membrane prolapse (2008)
  • Author(s): Kanai M, Ashida T, Ohira S, Osada R, Konishi I
  • Journal Title: J Obstet Gynaecol Res 34 Pages: 935-40
  • Peer Reviewed
• [Journal Article] Emerging drugs for ovarian cancer (2008)
  • Author(s): Sugiyama T, Konishi I..
  • Journal Title: Review. Expert Opin Emerg Drugs 13 Pages: 523-36
  • Peer Reviewed
• [Journal Article] Japan Clinical Oncology Group. Phase III trial of upfront debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0602 (2008)
  • Author(s): Onda T, Matsumoto K, Shibata T, Sato A, Fukuda H, Konishi I, Kamura T, Yoshikawa H
  • Journal Title: Jpn J Clin Oncol. 38 Pages: 74-7
  • Peer Reviewed
• [Journal Article] Malignant transformation of mature cystic teratoma of the ovary including three cases occurring during follow-up period (2008)
  • Author(s): Yamaguchi K, Mandai M, Fukuhara K, Higuchi T, Hamanishi J, Takakura K, Fujii S.
  • Journal Title: Oncol Rep 19 Pages: 705-11
  • Peer Reviewed
• [Journal Article] Intractable recurrent cervical cancer with pelvic bone involvement successfully treated with external hemipelvectomy (2008)
  • Author(s): Hamanishi J, Higuchi T, Mandai M, Fukuhara K, An M, Nakayama T, Takakura K, Fujii S.
  • Journal Title: J Obstet Gynaecol Res. 34 Pages: 112-6
  • NAID: 10021250457
  • Peer Reviewed
• [Journal Article] Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: utilization for ovarian cancer treatment (2008)
  • Author(s): Matsumura N, Mandai M, Hamanishi J, Yamaguchi K, Fukuhara K, Yagi H, Higuchi T, Takakura K, Fujii S.
  • Journal Title: Oncol Rep 19 Pages: 505-15
  • Peer Reviewed
• [Journal Article] Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress (2008)
  • Author(s): Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K, Fujii S.
  • Journal Title: Clin Cancer Res. 14 Pages: 32-40
  • Peer Reviewed
• [Journal Article] Overexpression of RhoA enhances peritoneal dissemination : RhoA suppression with Lovastatin may be useful for ovarian cancer. (2008)
  • Author(s): Horiuchi A, Kikuchi N, Osada R, Wang C, Hayashi A, Nikaido T, Konishi I.
  • Journal Title: Cancer Science 99 Pages: 2532-2539
  • NAID: 10024014761
  • Peer Reviewed
• [Journal Article] Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women (2007)
  • Author(s): Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, Nakanishi T, Sasaki H, Saji F, Iwasaka T, Hatae M, Kodama S, Saito T, Terakawa N, Yaegashi N, Hiura M, Sakamoto A, Tsuda H, Fukunaga M, Kamura T.
  • Journal Title: J Clin Oncol. 25 Pages: 2798-803
  • Peer Reviewed
• [Journal Article] Transplantation of preserved human amniotic membrane for bladder augmentation in rats (2007)
  • Author(s): Iijima K, Igawa Y, Imamura T, Moriizumi T, Nikaido T, Konishi I, Nishizawa O.
  • Journal Title: Tissue Eng. 13 Pages: 513-24
  • Peer Reviewed
• [Journal Article] Anatomic identification and functional outcomes of the nerve sparing Okabayashi radical hysterectomy (2007)
  • Author(s): Fujii S, Takakura K, Matsumura N, Higuchi T, Yura S, Mandai M, Baba T, Yoshioka S.
  • Journal Title: Gynecol Oncol 107 Pages: 4-13
  • Peer Reviewed
• [Journal Article] Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity (2007)
  • Author(s): Baba T, Mori S, Matsumura N, Kariya M, Murphy SK, Kondoh E, Kusakari T, Kuroda H, Mandai M, Higuchi T, Takakura K, Fukuda MN, Fujii S.
  • Journal Title: Biochem Biophys Res Commun 360 Pages: 363-9
  • Peer Reviewed
• [Journal Article] Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma (2007)
  • Author(s): Osada R, Horiuchi A, Kikuchi N, Yoshida J, Hayashi A, Ota M, Katsuyama Y, Melillo G, Konishi I.
  • Journal Title: Hum Pathol 38 Pages: 1310-20
  • Peer Reviewed
• [Journal Article] Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition (2007)
  • Author(s): Baba T, Kariya M, Higuchi T, Mandai M, Matsumura N, Kondoh E, Miyanishi M, Fukuhara K, Takakura K, Fujii S.
  • Journal Title: Gynecol Oncol 105 Pages: 703-11
  • Peer Reviewed
• [Journal Article] Hedgehog signal pathway is activated in ovarian carcinomas correlating with the cell proliferation: Its inhibition leads to the growth suppression and apoptosis. (2007)
  • Author(s): Chen XJ, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T, Konishi I
  • Journal Title: Cancer Science 98 Pages: 68-76
  • Peer Reviewed
• [Journal Article] Overexpression of Hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells. (2007)
  • Author(s): Feng YZ, Shiozawa T, Miyamoto T, Kashima H, Kurai M, Suzuki A, Jiang YS, Konishi I
  • Journal Title: Clinical Cancer Research 13 Pages: 1389-1398
  • Peer Reviewed
• [Journal Article] LH/hCG action and development of ovarian cancer: A short review on biological and clinical/epidemiological aspects. (2007)
  • Author(s): Mandai M, Konishi I, Kuroda H, FujiiS
  • Journal Title: Molecular and Cellular Endocrinology 38 Pages: 1310-1320
  • Peer Reviewed
• [Journal Article] Expression of hypoxia-inducible factor-la (HIF-1α), HIF-2α and von Hippel-Lindau (VHL) protein in epithelial ovarian neoplasms: Nuclear expression of HIF-1α is an independent prognostic factor in ovarian carcinoma. (2007)
  • Author(s): Osada R, Horiuchi A, Kikuchi N, Yoshida J, Hayashi A, Ota M, Katsuyama M, Mellilo G, Konishi I
  • Journal Title: Human Pathology 38 Pages: 1310-1320
  • Peer Reviewed
• [Presentation] 卵巣癌における化学療法感受性バイオマーカーの開発と組織型による分子標的の同定- 治療個別化に向けたBioinformatics の応用 (2009)
  • Author(s): 松村謙臣
  • Organizer: 第61回日本産科婦人科学会シンポジウム
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2009-04-04
• [Presentation] 卵巣癌の発生および進展のエピジェネティクス解析-BRCA1 メチル化およびS100A4 脱メチル化の臨床的意義 (2008)
  • Author(s): 堀内晶子
  • Organizer: 第60回日本産科婦人科学会シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-04-14
• [Presentation] 卵巣癌の発生および進展のエピジェネティクス解析-BRCA1メチル化およびS100A4脱メチル化の臨床的意義. (2008)
  • Author(s): 堀内 晶子
  • Organizer: 第60回日本産科婦人科学会 シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-04-14
• [Presentation] 卵巣癌における化学療法感受性バイオマーカーの開発と組織型による分子標的の同定-治療個別化に向けたBioinformaticsの応用 (2008)
  • Author(s): 松村謙臣
  • Organizer: 第61回日本産科婦人科学会 シンポジウム
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-04-04
• [Book] よくわかる卵巣癌のすべて (2007)
  • Author(s): 安田允、伊東和子、塩沢丹里、小西郁生
  • Total Pages: 514
  • Publisher: 永井書店