Targeting of endometrial cancer with highly metastatic phenotype

2010 Fiscal Year Final Research Report

• Project/Area Number: 21791552
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: Kyoto University
• Principal Investigator: BABA Tsukasa Kyoto University, 医学研究科, 助教 (60508240)
• Project Period (FY): 2009 – 2010
• Keywords: 婦人科腫瘍学

Research Abstract

Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, KISS1 (kisspeptin), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (p<0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC, These data suggest that metastin-10 may be effective at inhibiting metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression.

Research Products

• [Journal Article] Endometrial cancer implanted within a cesarean section scar. (2011)
  • Author(s): Baba T, Mandai M, Yamanishi Y, Suzuki A,Kang HS, Konishi I.
  • Journal Title: J Obstet Gynaecol Res. 37(3) Pages: 245-249
• [Journal Article] GPR54 Is a Target for Suppression of Metastasis in Endometrial Cancer. (2011)
  • Author(s): Kang HS, Baba T, Mandai M, Matsumura N, Hamanishi J, Kharma B, Kondoh E, Yoshioka Y, Oishi S, Fujii N, Murphy SK, Konishi I.
  • Journal Title: Mol Cancer Ther. 10(4) Pages: 580-590
• [Journal Article] Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer. (2011)
  • Author(s): Matsumura N, Huang Z, Mori S, Baba T, Fujii S, Konishi I, Iversen ES, Berchuck A, Murphy SK.
  • Journal Title: Genome Res. 21(1) Pages: 74-82
• [Journal Article] Distinguishing primary from secondary mucinous ovarian tumors : an algorithm using the novel marker DPEP1. (2011)
  • Author(s): Okamoto T, Matsumura N, Mandai M, Oura T, Yamanishi Y, Horiuchi A, Hamanishi J, Baba T, Koshiyama M, Shiozawa T, Konishi I.
  • Journal Title: Mod Pathol. 24(2) Pages: 267-276
• [Journal Article] Oct4 expression in immature teratoma of the ovary : relevance to histologic grade and degree of differentiation. (2010)
  • Author(s): Abiko K, Mandai M, Hamanishi J, Matsumura N, Baba T, Horiuchi A, Mikami Y, Yoshioka S, Wakasa T, Shiozawa T, Konishi I.
  • Journal Title: Am J Surg Pathol. 34(12) Pages: 1842-1848
• [Journal Article] Sorafenib efficacy in ovarian clear cell carcinoma revealed by transcriptome profiling. (2010)
  • Author(s): Matsumura N, Mandai M, Okamoto T, Yamaguchi K, Yamamura S, Oura T, Baba T, Hamanishi J, Kang HS, Matsui S, Mori S, Murphy SK, Konishi I.
  • Journal Title: Cancer Sci. 101(12) Pages: 2658-2663
• [Journal Article] Targeting slow-proliferating ovarian cancer cells. (2010)
  • Author(s): Kondoh E, Mori S, Yamaguchi K, Baba T, Matsumura N, Cory Barnett J, Whitaker RS, Konishi I, Fujii S, Berchuck A, Murphy SK.
  • Journal Title: Int J Cancer. 126(10) Pages: 2448-2456
• [Journal Article] Expression signatures of TP53 mutations in serous ovarian cancer s. (2010)
  • Author(s): Bernardini MQ, Baba T, Lee PS, Barnett JC, Sfakianos GP, Secord AA, Murphy SK, Iversen E, Marks JR, Berchuck A.
  • Journal Title: BMC Cancer. 15 Pages: 237
• [Journal Article] Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes. (2010)
  • Author(s): Yamaguchi K, Mandai M, Oura T, Matsumura N, Hamanishi J, Baba T, Matsui S, Murphy SK, Konishi I.
  • Journal Title: Oncogene. 29(12) Pages: 1741-1752
• [Journal Article] Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype. (2010)
  • Author(s): Barnett JC, Bean SM, Whitaker RS, Kondoh E, Baba T, Fujii S, Marks JR, Dressman HK, Murphy SK, Berchuck A.
  • Journal Title: Gynecol Oncol. 116(3) Pages: 556-562
• [Journal Article] Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer. (2010)
  • Author(s): Lee PS, Teaberry VS, Bland AE, Huang Z, Whitaker RS, Baba T, Fujii S, Secord AA, Berchuck A, Murphy SK.
  • Journal Title: Int J Cancer. 126(6) Pages: 1378-1389
• [Journal Article] Minimal deviation mucinous adenocarcinoma ('adenoma malignum') of the uterine corpus. (2010)
  • Author(s): Abiko K, Baba T, Ogawa M, Mikami Y, Koyama T, Mandai M, Konishi I.
  • Journal Title: Pathol Int. 60(1) Pages: 42-47
• [Journal Article] Activated local immunity by CC chemokine ligand 19-transduced embryonic endothelial progenitor cells suppresses metastasis of murine ovarian cancer. (2010)
  • Author(s): Hamanishi J, Mandai M, Matsumura N, Baba T, Yamaguchi K, Fujii S, Konishi I.
  • Journal Title: Stem Cells. 28(1) Pages: 164-173
• [Journal Article] Ovarian cancer in endometriosis : molecular biology, pathology, and clinical management. (2009)
  • Author(s): Mandai M, Yamaguchi K, Matsumura N, Baba T, Konishi I.
  • Journal Title: Int J Clin Oncol. 14(5) Pages: 383-391
• [Journal Article] Anchorage-independent cell growth signature identifies tumors with metastatic potential. (2009)
  • Author(s): Mori S, Chang JT, Andrechek ER, Matsumura N, Baba T, Yao G, Kim JW, Gatza M, Murphy S, Nevins JR.
  • Journal Title: Oncogene. 28(31) Pages: 2796-2805
• [Journal Article] MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition. (2009)
  • Author(s): Ding X, Mohd AB, Huang Z, Baba T, Bernardini MQ, Lyerly HK, Berchuck A, Murphy SK, Buermeyer AB, Devi GR.
  • Journal Title: Br J Cancer. 101(2) Pages: 269-277
• [Presentation] The novel role of GPR54 in endometrial cancer. (2010)
  • Author(s): Kang HS, Baba T, Konishi I, et al.
  • Organizer: 69^<th> Annual Meeting of the Japanese Cancer Association.
  • Place of Presentation: Osaka
  • Year and Date: 2010-09-23
• [Presentation] Fluedarabine as a possible alternative treatment in endometrial cancer type II by interfering STAT1 pathway. (2010)
  • Author(s): Kang HS, Baba T, Konishi I, et al.
  • Organizer: 69^<th> Annual Meeting of the Japanese Cancer Association.
  • Place of Presentation: Osaka
  • Year and Date: 2010-09-23
• [Presentation] Metastin-10 suppresses invasion of endometrial cancer cells. (2010)
  • Author(s): Kharma B, Baba T, Konishi I, et al.
  • Organizer: The 6th International Symposium on Hormonal Oncogenesis.
  • Place of Presentation: Chiba
  • Year and Date: 2010-09-12
• [Presentation] STAT1 and p53 status on chemotherapy-induced apoptosis in endometrial cancer. (2010)
  • Author(s): Kharma B, Baba T, Konishi I, et al.
  • Organizer: 14^<th> International Congress of Immunology.
  • Place of Presentation: Kobe
  • Year and Date: 2010-08-22
• [Presentation] 子宮体癌における転移抑制ペプチドmetastinの有用性 (2010)
  • Author(s): 馬場長、姜賢淑、小西郁生
  • Organizer: 第48回日本婦人科腫瘍学会学術集会
  • Place of Presentation: 筑波
  • Year and Date: 2010-07-08
• [Presentation] 子宮体癌におけるmetastin-GPR54 axis (2010)
  • Author(s): 姜賢淑、馬場長、小西郁生
  • Organizer: 第15回生殖医学フォーラム
  • Place of Presentation: 唐津
  • Year and Date: 2010-06-04
• [Presentation] Metastin-10 suppresses invasion of endometrial cancer cells. (2010)
  • Author(s): Baba T, Kang HS, Konishi I, et al.
  • Organizer: 41^<at> Annual Meeting on Women's Cancer.
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2010-03-15
• [Presentation] The novel role of GPR54 in endometrial cancer. (2009)
  • Author(s): Kang HS, Baba T, Konishi I, et al.
  • Organizer: 68^<th> Annual Meeting of the Japanese Cancer Association.
  • Place of Presentation: Yokohama
  • Year and Date: 2009-10-01
• [Presentation] 子宮体癌における転移抑制因子受容体GPR54の発現と機能 (2009)
  • Author(s): 姜賢淑、馬場長、小西郁生
  • Organizer: 第8回日本婦人科がん分子標的研究会学術集会
  • Place of Presentation: 博多
  • Year and Date: 2009-07-03
• [Book] 子宮体がん:転移リスクとその取り扱い(細胞工学別冊がん転移:臨床と研究の羅針盤) (2010)
  • Author(s): 馬場長、万代昌紀、小西郁生
  • Total Pages: 83-88
  • Publisher: 秀潤社
• [Book] 子宮ポリープ状異型腺筋腫(atypical polypoid adenomyoma, APAM)の病態と診断～日常診療で気をつけるべきこと～(OG scope:産婦人科医のための定期情報誌,v.1, no.2) (2010)
  • Author(s): 馬場長、小西郁生
  • Publisher: 医科学出版社