Establishment of in vitro carcinogenesis model of ovarian low-grade serous carcinoma

• Project/Area Number: 18K09229
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Shimane University
• Principal Investigator: Kentaro Nakayama 島根大学, 学術研究院医学・看護学系, 准教授 (70346401)
• Co-Investigator(Kenkyū-buntansha): 京 哲 島根大学, 学術研究院医学・看護学系, 教授 (50272969)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 卵巣癌 / 発癌 / 低異型度 / 漿液性癌 / がん遺伝子 / 多段階発癌 / がん抑制遺伝子 / 細胞不死化 / 卵巣低異型度腫瘍 / 邦人 / 遺伝子変異 / KRAS / PIK3CA / 低異型度漿液性癌 / 発癌モデル / 癌遺伝子

Outline of Final Research Achievements

Serous cystadenoma epithelial cells have been proposed to be the derivation of low grade serous ovarian carcinoma. Whereas several genetic diversifications are known to be involved in development of LGSC, but the fundamental requirements are unclear. We aimed to bracelet oncogenic mutations that responsible for LGSC development in a stepwise model, by using immortalized serous cystadenoma (SCA) epithelial cells. SCA were isolated from clinical sample and immortalized by overexpression of cyclin D1, CDK4R24C and hTERT. Transformed SCA epithelial cells with KRAS MT and PIK3CA MT, formed tumors into nude mouse that were grossly, histologically, and immunohistochemically analogous to human tumor. Thus, KRAS MT and PIK3CA MT were classified as the basal obligation for LGSC development. Current in vitro carcinogenesis model suggested that KRAS MT and PIK3CA MT is responsible for micropapillary stages of LGSC development.

Academic Significance and Societal Importance of the Research Achievements

卵巣低異型度漿液性癌は卵巣漿液性嚢胞腺腫を発生起源とする仮説があるがその詳細は不明である。卵巣漿液性嚢胞腺腫の不死化細胞を樹立し、in vitro発癌モデルを構築し、卵巣低異型度漿液性癌の発癌分子機構を明らかにすることを目的とした。HOVcyst1(不死化卵巣漿液性嚢胞腺腫細胞)への変異型PIK3CAおよび変異型KRAS の遺伝子導入により卵巣低異型度漿液性癌のin vitro発癌モデル構築に成功した。卵巣低異型度漿液性癌の発癌経路としてPIK3CA/AKT/mTORおよびKRAS/BRAF/ERK経路の双方の活性化が必要であることが示唆された。

Research Products

• [Journal Article] Whole-Exome Sequencing of Rare Site Endometriosis-Associated Cancer. (2021)
  • Author(s): Kurose S, Nakayama K, Razia S, Ishikawa M, Ishibashi T, Yamashita H, Sato S, Sakiyama A, Yoshioka S, Kobayachi M, Nakayama S, Otsuki Y, Ishikawa N, Kyo S.
  • Journal Title: Diseases (Basel, Switzerland) Volume: 9 Issue: 1 Pages: 14-14
  • DOI: 10.3390/diseases9010014
  • Peer Reviewed / Open Access
• [Journal Article] Pregnancy by Assisted Reproductive Technology Is Associated with Shorter Telomere Length in Neonates. (2020)
  • Author(s): Minamoto T, Nakayama K, Ishibashi T, Ishikawa M, Nakamura K, Yamashita H, Shanta K, Mahmud HM, Razia S, Iida K, Nakamura T, Kanda H, Kyo S.
  • Journal Title: International journal of molecular sciences Volume: 21 Issue: 24 Pages: 9688-9688
  • DOI: 10.3390/ijms21249688
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence and Associated Factors of Malnutrition and Sarcopenia in a Daycare Facility: A Cross-Sectional Study. (2020)
  • Author(s): Shiota A, Nakayama N, Saito Y, Maeda T, Maeda Y, Nakayama K.
  • Journal Title: Healthcare (Basel, Switzerland) Volume: 8 Issue: 4 Pages: 576-576
  • DOI: 10.3390/healthcare8040576
  • Peer Reviewed / Open Access
• [Journal Article] Nucleus Accumbens-Associated Protein 1 Binds DNA Directly through the BEN Domain in a Sequence-Specific Manner. (2020)
  • Author(s): Nakayama N, Sakashita G, Nagata T, Kobayashi N, Yoshida H, Park SY, Nariai Y, Kato H, Obayashi E, Nakayama K, Kyo S, Urano T.
  • Journal Title: Biomedicines Volume: 8 Pages: 608-608
  • Peer Reviewed / Open Access
• [Journal Article] Pathological findings in the endometrium after microwave endometrial ablation. (2020)
  • Author(s): Nakayama K, Sultana R, Ishibashi T, Ishikawa M, Yamashita H, Nakamura K, Sawada K, Yoshimura Y, Tatsumi N, Kurose S, Minamoto T, Iida K, Ishikawa N, Kyo S
  • Journal Title: Scientific reports Volume: 10 Issue: 1 Pages: 20766-20766
  • DOI: 10.1038/s41598-020-77594-x
  • Peer Reviewed / Open Access
• [Journal Article] Mucinous borderline ovarian tumors with BRAF V600E mutation may have low risk for progression to invasive carcinomas (2020)
  • Author(s): hnishi K, Nakayama K, Ishikawa M, Ishibashi T, Yamashita H, Nakamura K, Minamoto T, Iida K, Razia S, Ishikawa N, Kyo S.
  • Journal Title: Arch Gynecol Obstet Volume: 302 Issue: 2 Pages: 487-495
  • DOI: 10.1007/s00404-020-05638-8
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Value of Peripheral Blood Lymphocyte Telomere Length in Gynecologic Malignant Tumors. (2020)
  • Author(s): Shanta K, Nakayama K, Ishikawa M, Ishibashi T, Yamashita H, Sato S, Sasamori H, Sawada K, Kurose S, Mahmud HM, Razia S, Iida K, Ishikawa N, Kyo S
  • Journal Title: Cancers Volume: 12 Issue: 6 Pages: 1469-1469
  • DOI: 10.3390/cancers12061469
  • Peer Reviewed / Open Access
• [Journal Article] Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma. (2020)
  • Author(s): Kohei Nakamura, Eriko Aimono, Shigeki Tanishima, Mitsuho Imai, Akiko Kawano Nagatsuma, Hideyuki Hayashi, Yuki Yoshimura, Kentaro Nakayama, Satoru Kyo, Hiroshi Nishihara
  • Journal Title: Diagnostics Volume: 10 Pages: 1-1
  • Peer Reviewed / Open Access
• [Journal Article] The fallopian tube as origin of ovarian cancer: Change of diagnostic and preventive strategies. (2020)
  • Author(s): Satoru Kyo, Noriyoshi Ishikawa, Kohei Nakamura, Kentaro Nakayama
  • Journal Title: Cancer medicine Volume: 9 Issue: 2 Pages: 421-431
  • DOI: 10.1002/cam4.2725
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Frequency of PIK3CA Mutations in Low-Grade Serous Ovarian Carcinomas of Japanese Patients. (2019)
  • Author(s): Tomoka Ishibashi, Kentaro Nakayama, Sultana Razia, Masako Ishikawa, Kohei Nakamura, Hitomi Yamashita, Puja Dey, Koji Iida, Hiroko Kurioka, Satoru Nakayama, Yoshiro Otsuki, Noriyoshi Ishikawa, Satoru Kyo
  • Journal Title: Diagnostics Volume: 10 Pages: 1-1
  • Peer Reviewed / Open Access
• [Journal Article] Sarcopenic Factors May Have No Impact on Outcomes in Ovarian Cancer Patients. (2019)
  • Author(s): Naomi Nakayama, Kentaro Nakayama, Kohei Nakamura, Sultana Razia, Satoru Kyo
  • Journal Title: Diagnostics Volume: 9 Pages: 1-1
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between Microsatellite Instability, Immune Cells Infiltration, and Expression of Immune Checkpoint Molecules in Ovarian Carcinoma: Immunotherapeutic Strategies for the Future. (2019)
  • Author(s): Hitomi Yamashita, Kentaro Nakayama, Masako Ishikawa, Tomoka Ishibashi, Kohei Nakamura, Kiyoka Sawada, Yuki Yoshimura, Nagisa Tatsumi, Sonomi Kurose, Toshiko Minamoto, Kouji Iida, Sultana Razia, Noriyoshi Ishikawa, Satoru Ky
  • Journal Title: International journal of molecular sciences Volume: 20 Issue: 20 Pages: 1-1
  • DOI: 10.3390/ijms20205129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological and biological analysis of PIK3CA mutation and amplification in cervical carcinomas. (2019)
  • Author(s): Sultana Razia, Kentaro Nakayama, Kohei Nakamura, Tomoka Ishibashi, Masako Ishikawa, Toshiko Minamoto, Kouji Iida, Yoshiro Otsuki, Satoru Nakayama, Noriyoshi Ishikawa, Satoru Kyo
  • Journal Title: Experimental and therapeutic medicine Volume: 18 Pages: 2278-2284
  • DOI: 10.3892/etm.2019.7771
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies). (2019)
  • Author(s): Ruriko Ono, Kentaro Nakayama, Kohei Nakamura, Hitomi Yamashita, Tomoka Ishibashi, Masako Ishikawa, Toshiko Minamoto, Sultana Razia, Noriyoshi Ishikawa, Yoshiro Otsuki, Satoru Nakayama, Hideyuki Onuma, Hiroko Kurioka, Satoru Kyo
  • Journal Title: International journal of molecular sciences Volume: 20 Issue: 15 Pages: 1-1
  • DOI: 10.3390/ijms20153744
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TERT promoter mutation is rare event in ovarian clear cell carcinomas in Japanese population. (2019)
  • Author(s): Katagiri H, Nakayama K＊, Nakamura K, Sultana R, Sato E, Ishibashi T, Ishikawa M, Minamoto T, Iida K, Otsuki Y, Nakayama S, Ishikawa N, Kyo S
  • Journal Title: Eur J Gynaecol Oncol Volume: 40 Pages: 220-223
  • Peer Reviewed
• [Journal Article] High frequency of POLE mutations in synchronous endometrial and ovarian carcinoma. (2018)
  • Author(s): Ishikawa M, Nakayama K＊, Nakamura K, Ono R, Yamashita H, Ishibashi T, Minamoto T, Iida K, Razia S, Ishikawa N, Kyo S.
  • Journal Title: Hum Pathol Volume: 18 Pages: 30424-30426
  • DOI: 10.1016/j.humpath.2018.11.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methylomic analysis of ovarian cancers identifies tumor-specific alterations readily detectable in early precursor lesions. (2018)
  • Author(s): Pisanic T, Lin SF, Yen TT, Athamanolap P, Nakayama K, Cope L, Wang TH, Shih IM, Wang TL
  • Journal Title: Clin Cancer Res Volume: 24 Issue: 24 Pages: 6536-6547
  • DOI: 10.1158/1078-0432.ccr-18-1199
  • Peer Reviewed
• [Journal Article] Affinity-purified DNA-based mutation profiles of endometriosis-related ovarian neoplasms in Japanese patients. (2018)
  • Author(s): Ishikawa M, Nakayama K, Nakamura K, Ono R, Sanuki K, Yamashita H, Ishibashi T, Minamoto T, Iida K, Razia S, Ishikawa N, Kyo S.
  • Journal Title: Oncotarget Volume: 9(19) Issue: 19 Pages: 14754-14763
  • DOI: 10.18632/oncotarget.24546
  • Peer Reviewed / Open Access
• [Journal Article] Detection of circulating tumor cells in cervical cancer using a conditionally (2017)
  • Author(s): Takakura M, Matsumoto T, Nakamura M, Mizumoto Y, Myojyo S, Yamazaki R, Iwadare
  • Journal Title: Cancer Sci.ence Volume: 109(1) Issue: 1 Pages: 231-240
  • DOI: 10.1111/cas.13449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 稀少部位子宮内膜症の悪性転化例における発癌ドライバー遺伝子の検討 (2021)
  • Author(s): 黒瀬 苑水, 中山 健太郎, 石川 雅子, 石橋 朋佳, 山下 瞳, 笹森 博貴, 澤田 希代加, 佐藤 誠也, 太田 啓明, 安藤 正明, 崎山 明香, 吉岡 信也, 小林 光紗, 中山 理, 大月 寛郎, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] 急激な進行を認めた再発卵巣粘液性境界悪性腫瘍の一例 (2021)
  • Author(s): 辰巳 渚, 中山 健太郎, 石川 雅子, 石橋 朋佳, 山下 瞳, 笹森 博貴, 澤田 希代加, 黒瀬 苑水, 佐藤 誠也, 青木 昭和, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] BRCA2遺伝子の生殖細胞系列変異を認めた卵巣粘液性癌の一例 (2021)
  • Author(s): 澤田 希代加, 中山 健太郎, 佐藤 誠也, 黒瀬 苑水, 中村 秋穂, 笹森 博貴, 山下 瞳, 石橋 朋佳, 石川 雅子, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] CARG scoreを用いた高齢者の化学療法有害事象発生リスクの検討 (2021)
  • Author(s): 笹森 博貴, 中山 健太郎, 石橋 朋佳, 黒瀬 苑水, 澤田 希代加, 中村 秋穂, 山下 瞳, 原 友美, 佐藤 絵美, 石川 雅子, 佐藤 誠也, 折出 亜希, 皆本 敏子, 金崎 春彦, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] 卵巣高異型度漿液性癌における多段階腫瘍形成の統合マルチオミックス解析 (2020)
  • Author(s): 同前 愛, 小松 正明, 町野 英徳, 中村 康平, 金子 修三, 生水 貫人, 浅田 健, 千代田 達幸, 中山 健太郎, 青木 大輔, 京 哲, 浜本 隆二
  • Organizer: 日本癌学会
• [Presentation] Precision medicineクリニカルシークエンスの現状と課題 がんゲノム医療連携病院でのがんゲノム医療センターの現状 (2019)
  • Author(s): 中山 健太郎, 中村 康平, 石川 雅子, 石橋 朋佳, 山下 瞳, 吉村 由紀, 澤田 希代加, 小野 瑠璃子, 辰巳 渚, 黒瀬 苑水, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] Genestic heterogeneityがprecision medecineに与える影響 サンプリング部位の選択に対する警鐘 (2019)
  • Author(s): 吉村 由紀, 中山 健太郎, 中村 康平, 黒瀬 苑水, 辰巳 渚, 澤田 希代加, 山下 瞳, 石橋 朋佳, 石川 雅子, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] 性索間質性腫瘍に類似したエストロゲン産生卵巣類内膜腺癌の分子生物学的検討 (2019)
  • Author(s): 小野 瑠璃子, 中山 健太郎, 中村 康平, 石橋 朋佳, 石川 雅子, 皆本 敏子, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] 低悪性度漿液性癌の発癌過程におけるOSEの卵管上皮化生について (2019)
  • Author(s): 中村 康平, 中山 健太郎, 澤田 希代加, 吉村 由紀, 山下 瞳, 石橋 朋佳, 皆本 敏子, 石川 雅子, 京 哲
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] 漿液性嚢胞腺腫の起源について ―低異型度漿液性癌の発癌機構の解明に向けてー (2018)
  • Author(s): 中村康平、中山健太郎、石川雅子、石橋朋佳、山下瞳、小野瑠璃子、笹森博貴、中村秋穂、吉村由紀、飯田幸司、スルタナ ラジア、フセイン モハメド モハマド、シャンタ カムルンナハル、皆本敏子、京哲
  • Organizer: 第3回 三大学コンソーシアム
• [Presentation] ARID1A変異を基盤としたEndometriosis-related ovarian neoplasms（ERONs）のin vitro発癌モデルの構築 (2018)
  • Author(s): 石川雅子、中山健太郎、笹森博貴、小野瑠璃子、大西薫、山下瞳、中村康平、
  • Organizer: 第3回 三大学コンソーシアム
• [Presentation] 子宮頸部腺癌における免疫チェックポイント分子発現の検討 (2018)
  • Author(s): 石川雅子、中山健太郎、笹森博貴、小野瑠璃子、大西薫、山下瞳、中村康平、石橋朋佳、皆本敏子、Razia Sulutana、飯田幸司、京哲
  • Organizer: 第70回目日本産科婦人科学会学術講演会
• [Remarks] 島根大学産婦人科 婦人科腫瘍研究室
  • URL: http://www.shimane-u-obgyn.jp/study/837