Elucidating the mechanism of resistance to chemotherapy in gynecologic cancer based on intratumor heterogeneity

• Project/Area Number: 15K15598
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Niigata University
• Principal Investigator: Enomoto Takayuki 新潟大学, 医歯学系, 教授 (90283754)
• Co-Investigator(Kenkyū-buntansha): 吉原 弘祐 新潟大学, 医歯学系, 助教 (40547535) ; 加嶋 克則 新潟大学, 医歯学総合病院, 特任教授 (50345500) ; 関根 正幸 新潟大学, 医歯学系, 准教授 (70345502) ; 石黒 竜也 新潟大学, 医歯学総合病院, 助教 (80625690)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: intratumor heterogeneity / cancer genome / spheroid / Intratumor heterogeneity

Outline of Final Research Achievements

In this study, we generated total 11 spheroid cultures derived from gynecologic cancers. Before genomic analyses for spheroid cultures, we focused on Sex-determining region Y-box 2 (SOX2), which is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells, to clarify the significance of SOX2 expression in endometrial cancer. SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

Research Products

• [Journal Article] Establishment and characterization of an in vitro model of ovarian cancer stem-like cells with an enhanced proliferative capacity. (2016)
  • Author(s): Ishiguro T, Sato A, Ohata H, Ikarashi Y, Takahashi R, Ochiya T, Yoshida M, Tsuda H, Onda T, Kato T, Kasamatsu T, Enomoto T, Tanaka K, Nakagama H, Okamoto K.
  • Journal Title: Cancer Research Volume: 76 Issue: 1 Pages: 150-160
  • DOI: 10.1158/0008-5472.can-15-0361
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The randomized phase 3 trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG Trial. (2016)
  • Author(s): Sugiyama T, Okamoto A, Enomoto T, Hamano T, Aotani E, Terao Y, Suzuki N, Mikami M, Yaegashi N, Kato K, Yoshikawa H, Yokoyama Y, Tanabe H, Nishino K, Nomura H, Kim JW, Kim BG, Pignata S, Alexandre J, Green J, Isonishi S, Terauchi F, Fujiwara K, Aoki D.
  • Journal Title: J Clin Oncol Volume: 34 Issue: 24 Pages: 2881-2887
  • DOI: 10.1200/jco.2016.66.9010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Single-dose intra- arterial neoadjuvant chemotherapy while waiting for radical hysterectomy for stage IB-IIB cervical cancer. (2016)
  • Author(s): Yoshino K, Hosoi A, Osuga K, Enomoto T, Ueda Y, Sawada K, Mabuchi S, Kobayashi E, Matsuo K, Kimura T.
  • Journal Title: Mol Clin Oncol. Volume: 4 Issue: 6 Pages: 1068-1072
  • DOI: 10.3892/mco.2016.846
  • Peer Reviewed
• [Journal Article] Association of Low-Dose Aspirin and Survival of Women With Endometrial Cancer. (2016)
  • Author(s): Matsuo K, Cahoon SS, Yoshihara K, Shida M, Kakuda M, Adachi S, Moeini A, Machida H, Garcia-Sayre J, Ueda Y, Enomoto T, et al.
  • Journal Title: Obstet Gynecol. Volume: 128 Issue: 1 Pages: 127-37
  • DOI: 10.1097/aog.0000000000001491
  • Peer Reviewed
• [Journal Article] Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. (2016)
  • Author(s): Nakaoka H, Gurumurthy A, Hayano T, Ahmadloo S, Omer WH, Yoshihara K, Yamamoto A, Kurose K, Enomoto T, Akira S, Hosomichi K,, Inoue I.
  • Journal Title: PLoS Genet. Volume: 1 Issue: 4 Pages: 1-23
  • DOI: 10.1371/journal.pgen.1005893
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Novel Histopathological Classification of High-Grade Serous Ovarian Carcinoma Correlated with Prognostically Distinct Gene Expression Subtypes. (2016)
  • Author(s): Murakami R, Matsumura N, Mandai M, Yoshihara K, Tanabe H, Nakai H, Yamanoi K, Abiko K, Yoshioka Y, Hamanishi J, Yamaguchi K, Baba T, Koshiyama M, Enomoto T, Okamoto A, Murphy SK, Mori S, Mikami Y, Minamiguchi S, Konishi I
  • Journal Title: Am J Pathol. Volume: 186 Issue: 5 Pages: 1103-13
  • DOI: 10.1016/j.ajpath.2015.12.029
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mothers' attitudes in Japan regarding cervical cancer screening correlates with intention to recommend cervical cancer screening for daughters. (2016)
  • Author(s): Egawa-Takata T, Ueda Y, Tanaka Y, Morimoto A, Kubota S, Yagi A, Terai Y, Ohmichi M, Ichimura T, Sumi T, Murata H, Okada H, Nakai H, Mandai M, Yoshino K, Kimura T, Saito J, Kudo R, Sekine M, Enomoto T, Horikoshi Y, Takagi T, Shimura K.
  • Journal Title: Int J Clin Oncol. Volume: 21 Issue: 5 Pages: 962-968
  • DOI: 10.1007/s10147-016-0970-4
  • Peer Reviewed / Open Access
• [Journal Article] Similar protein expression profiles of ovarian and endometrial high-grade serous carcinomas. (2016)
  • Author(s): Hiramatsu K, Yoshino K, Serada S, Yoshihara K, Hori Y, Fujimoto M, Matsuzaki S, Egawa-Takata T, Kobayashi E, Ueda Y, Morii E, Enomoto T, Naka T, Kimura T.
  • Journal Title: Br J Cancer. Volume: 114（5） Issue: 5 Pages: 554-561
  • DOI: 10.1038/bjc.2016.27
  • Peer Reviewed
• [Journal Article] A phase II study of postoperative concurrent carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy followed by consolidation chemotherapy in surgically treated cervical cancer patients with positive pelvic lymph nodes. (2016)
  • Author(s): Mabuchi S, Isohashi F, Yokoi T, Takemura M, Yoshino K, Shiki Y, Ito K, Enomoto T, Ogawa K, Kimura T.
  • Journal Title: Gynecol Oncol. Volume: 141 Pages: 240-6
  • Peer Reviewed
• [Journal Article] Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. (2015)
  • Author(s): Matsuo K, Hasegawa K, Yoshino K, Murakami R, Hisamatsu T, Stone RL, Previs RA, Hansen JM, Ikeda Y, Miyara A, Hiramatsu K, Enomoto T, Fujiwara K, Matsumura N, Konishi I, Roman LD, Gabra H, Fotopoulou C, Sood AK.
  • Journal Title: Eur J Cancer Volume: 51(14) Pages: 1978-88
  • Peer Reviewed
• [Journal Article] Survival outcome of stage I ovarian clear cell carcinoma with lympho-vascular space invasion. (2015)
  • Author(s): Matsuo K, Yoshino K, Hasegawa K, Murakami R, Ikeda Y, Adachi S, Hiramatsu K, Yokoyama T, Nishimura M, Sheridan TB, Enomoto T, Fujiwara K, Matsumura N, Konishi I, Fotopoulou C, Roman LD, Sood AK.
  • Journal Title: Gynecol Oncol. Volume: 136(2) Pages: 198-204
  • Peer Reviewed
• [Journal Article] Novel kinase fusion transcripts found in endometrial cancer. (2015)
  • Author(s): Tamura R, Yoshihara K, Yamawaki K, Suda K, Ishiguro T, Adachi S, Okuda S, Inoue I, Verhaak RG, Enomoto T.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 18657-18657
  • DOI: 10.1038/srep18657
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CpG ODN potentiates the anti-tumor activity of anti-BST2 antibody. (2015)
  • Author(s): Hiramatsu, K., Serada, S., Kobiyama, K., Nakagawa, S., Morimoto, A., Matsuzaki, S., Ueda,Y., Fujimoto, M., Yoshino, K., Ishii, K., Enomoto, T., Kimura, T., Naka, T.
  • Journal Title: Cancer Science Volume: 106(10) Issue: 10 Pages: 474-82
  • DOI: 10.1111/cas.12738
  • Peer Reviewed / Open Access
• [Journal Article] Identification of novel exonic mobile element insertions in epithelial ovarian cancers. (2015)
  • Author(s): Hayano,T., Yamada,S., Hosomichi,K., Nakaoka,H., Yoshihara,K., Adachi.S. Kashima,K., Tanaka, K and Enomoto,T.& Inoue,I.
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15030-15030
  • DOI: 10.1038/hgv.2015.30
  • Peer Reviewed
• [Presentation] The significance of activated PI3K/AKT pathway in FGFR3-TACC3 fusion positive cervical cancer (2017)
  • Author(s): 田村 亮、吉原 弘祐、森 裕太郎、山脇 芳、須田 一暁、石黒 竜也、榎本 隆之
  • Organizer: American Association of Cancer Research Annual Meeting 2017
  • Place of Presentation: Washington DC,USA
  • Int'l Joint Research
• [Presentation] Identificat of therapeutically targetable FGFR-fusion genes in cervical cancer through RNA sequencing (2017)
  • Author(s): 田村 亮、吉原 弘祐、石黒 竜也、榎本 隆之
  • Organizer: 第69回日本産科婦人科学会学術講演会
  • Place of Presentation: 広島県立総合体育館 外（広島県広島市）
  • Int'l Joint Research
• [Presentation] 婦人科領域における分子標的治療の現況と将来 (2016)
  • Author(s): 榎本 隆之
  • Organizer: 第42回日本臨床細胞学会近畿連合会
  • Place of Presentation: ナレッジキャピタルコンベンションセンター（大阪府大阪市）
• [Presentation] 妊娠と子宮頸がん (2016)
  • Author(s): 榎本 隆之
  • Organizer: 第43回日本産婦人科医会学術集会
  • Place of Presentation: 万国津梁館（沖縄県名護市）
• [Presentation] 子宮頸がんについての最近の話題 (2016)
  • Author(s): 榎本 隆之
  • Organizer: 第4回新潟市医師会総会 第51回新潟市医師会臨床懇話会総会
  • Place of Presentation: 新潟東映ホテル（新潟県新潟市）
  • Invited
• [Presentation] 子宮体がんにおける幹細胞因子Sox2発現の意義 (2016)
  • Author(s): 森 裕太郎、山脇 芳、石黒 竜也、吉原 弘祐、榎本 隆之
  • Organizer: 第15回日本婦人科がん分子標的研究会
  • Place of Presentation: ニューオータニイン札幌（北海道札幌市）
• [Presentation] A proteomic analysis demonstrates similar expression pattern between ovarian and endometrial high-grade serous carcinoma beyond an organ (2015)
  • Author(s): Kosuke Hiramatsu, Kiyoshi Yoshino, Satoshi Serada, Kosuke Yoshihara, Minoru Fujimoto, Yutaka Ueda, Eiichi Morii, Takayuki Enomoto, Tetsuji Naka, Tadashi Kimura
  • Organizer: 24th Asian and Oceanic Congress of Obstetrics and Gynaecology
  • Place of Presentation: Borneo Convention Centre Kuching （Malaysia）
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] 卵巣および子宮体部のhigh- grade serous carcinoma の類似性の証明 (2015)
  • Author(s): 平松宏祐、榎本隆之、吉原弘祐、上田豊、吉野潔、森井英一、仲哲治、木村正
  • Organizer: 第67回日本産科婦人科学会学術講演会
  • Place of Presentation: パシフィコ横浜(神奈川県、横浜市)
  • Year and Date: 2015-04-10