Inappropriate Reprogramming Induce Carcinogenesis of Ovarian Embryonal Carcinoma

• Project/Area Number: 20K18169
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Yokohama City University
• Principal Investigator: Hayama Tomonari 横浜市立大学, 附属市民総合医療センター, 講師 (70819903)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 卵巣胚細胞性腫瘍 / 発癌 / リプログラミング / モデル動物 / 卵巣悪性腫瘍 / 卵巣胎児癌 / 生殖細胞

Outline of Research at the Start

卵巣胎児性癌はAYA世代の卵巣がんの半数を占める悪性腫瘍で、生物学的発生機序が分かっていないため早期発見の方法がない。若い進行癌患者さんは治療により妊娠できなくなってしまったり、治療の甲斐なく死に至るため、社会的損失は大きい。
本課題では、近年報告されたリプログラミングを体内で誘導できる動物モデルを用いて、卵巣内卵子に多能性を誘導しこの癌が発生するかどうか調べ、発生する時の卵巣組織内での遺伝子発現の変化を明らかにする。「発病トリガーは適切ではない卵巣組織内でのリプログラミングによる多能性獲得」であるという仮説が証明されれば、早期発見腫瘍マーカーの探索に大きな貢献が期待される。

Outline of Final Research Achievements

Ovarian embryonic carcinoma (EC) is tumor consisting of phenotypically immature germ cells. The origin of EC was hypothesized as oocytes in ovary. However, the origin and mechanisms of disease onset is still unclear because of no animal model of EC carcinogenesis. As novel EC animal model, we used ovaries of "reprogrammable animal" carrying inducible reprogramming genes. We induced reprogramming of ovaries in vivo, and clarified the origin and molecular mechanism of disease onset. The pre-meiosis oocytes under reprogramming, initially, simple cysts(SC) are formed, among which EC cell mass is formed. Few gene expression changes during reprogramming induce EC cells proliferation, accompanied by differentiated tissues. Those changes are similarly detected in human EC cell line. Our model provides an inducible animal model for carcinogenesis of ovarian EC from ovary. This model will be powerful research tool for mechanism of carcinogenesis, chemical treatment, and early cancer detection.

Academic Significance and Societal Importance of the Research Achievements

卵巣胚性癌（EC）はAYA世代に好発する卵巣悪性腫瘍であり、大部分の症例は進行癌で発見され、生命は助かるが妊孕性は失われることが多い。ECの発癌の原因はわかっておらず、早期発見法も確立されていない。我々の開発した発癌動物モデルは、卵巣からECの発癌を誘導する動物モデルを世界で初めて提供した。さらにこのモデルで、卵巣ECの発がんの形態学・分子生物学的機序を解明した。このモデルはECの早期発見方法開発や、化学療法開発などの研究で強力なツールとなることも見込まれる。また本研究は2023年5月に行われた第75回日本産婦人科学会学術総会の婦人科腫瘍部門でJSOG Congress Awardを受賞した。

Research Products

• [Journal Article] 【ミトコンドリア 疾患治療の新時代】生殖補助技術を用いた受精胚でのミトコンドリア病の根本治療戦略と展望 (2023)
  • Author(s): 葉山智工
  • Journal Title: 実験医学増刊号 Volume: Vol.41 No.5 Pages: 180-187
• [Journal Article] Outcomes of the study of intracytoplasmic sperm injection (ICSI) and sperm motility with microdissection testicular sperm extraction (2022)
  • Author(s): Murase Mariko、Arai Yuuka、Ueno Hiroe、Yamamoto Mizuki、Izumi Haruna、Takeshima Kazumi、Hayama Tomonari、Sakakibara Hideya、Yumura Yasushi、Miyagi Etsuko
  • Journal Title: Asian Journal of Andrology Volume: 24 Issue: 2 Pages: 221-221
  • DOI: 10.4103/aja202152
  • Peer Reviewed
• [Journal Article] The acceptance to germline gene therapy increased during <scp>COVID</scp> ‐19 pandemic among Japanese medical students (2022)
  • Author(s): Ijuin Akifumi、Hayama Tomonari、Sakakibara Hideya
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 48 Issue: 6 Pages: 1495-1496
  • DOI: 10.1111/jog.15246
  • Peer Reviewed
• [Journal Article] 【特集 受精と胚発生をめぐる話題】ミトコンドリア遺伝子異常とその治療 (2022)
  • Author(s): 葉山智工
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 29（1） Pages: 37-42
• [Journal Article] 不妊治療の保険適用拡大の意義－薬局薬剤師への影響を含めて (2022)
  • Author(s): 葉山智工 倉澤健太郎
  • Journal Title: 調剤と情報 Volume: Vol28、No13 Pages: 2192-2197
• [Journal Article] Fertility preservation immediately after therapeutic abortion results in multiple normal follicular growth with the absence of mature oocytes due to early luteinization: a case report and literature review (2021)
  • Author(s): Hamada Haru、Hayama Tomonari、Ijuin Akifumi、Miyakoshi Ai、Kasai Michi、Tochihara Shiori、Saito Marina、Nishi Mayuko、Ueno Hiroe、Yamamoto Mizuki、Komeya Mitsuru、Yumura Yasushi、Sakakibara Hideya、Miyagi Etsuko、Murase Mariko
  • Journal Title: Gynecological Endocrinology Volume: 37 Issue: 11 Pages: 1050-1053
  • DOI: 10.1080/09513590.2021.1950135
  • Peer Reviewed
• [Journal Article] Deleterious mtDNA Mutations are Common in Mature Oocytes. (2020)
  • Author(s): Hayama T, Ma H, Van Dyken C, Darby H, Koski A, Lee Y, Gutierrez NM, Yamada S, Li Y, Andrews M, Ahmed R, Liang D, Gonmanee T, Kang E, Nasser M, Kempton B, Brigande J, McGill TJ, Terzic A, Amato P, Mitalipov S.
  • Journal Title: Biol Reprod. Volume: 102 Issue: 3 Pages: 607-619
  • DOI: 10.1093/biolre/ioz202
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Inappropriate Reprogramming Induce Carcinogenesis of Ovarian Embryonal Carcinoma in Rodent Ovary (2023)
  • Author(s): Tomonari Hayama, Hideya Sakakibara, Etsuko Miyagi, Tomoyuki Yamaguchi
  • Organizer: 第75回日本産科婦人科学会学術講演会、東京
• [Presentation] High spontaneous abortions in ICSI pregnancies using fertility-preserving frozen sperm in patients with testicular germ cell tumor (TGCT) (2022)
  • Author(s): Haru Hamda, Tomonari Hayama, Akifumi Ijuin, Mizuki Yamamoto, Hiroe Ueno, Ai Miyakoshi, Mayuko Nishi, Marina Saito, Shiori Tochihara, Mitsuru Komeya, Teppei Takeshima, Shinnosuke Kuroda, Tomiki Saito, Miki Tanoshima, Kazumi Takeshima, Haruka Hamanoue, Hideya Sakakibara, Yasushi Yumura, Etsuko Miyagi & Mariko Murase
  • Organizer: ESHRE 2022 European Society of Human Reproduction and Embryology 38th annual meewting, Milan Italy
  • Int'l Joint Research
• [Presentation] 卵胞液中に存在するタンパク質Aと妊娠の関係性 (2022)
  • Author(s): 葉山智工，伊集院昌郁，上野寛枝，小堀宏樹，栃原しおり，末吉寿実鼓，濱田春，宮腰藍衣，齋藤満里奈，大池有紀，竹島徹平，榊原秀也，湯村寧，宮城悦子，村瀬真理子
  • Organizer: 第67回日本生殖医学会学術講演会、横浜
• [Presentation] Purifying selection for aneuploidy cells in mosaicism embryo at post-implantation stage. (2021)
  • Author(s): Tomonari Hayama, Akifumi Ijuin, Hiroe Ueno, Haru Hamada, Ai Miyakoshi, Mayuko Nishi, Marina Saito, Haruka Hamanoue, Mitsuru Komeya, Teppei Takeshima, Shinnosuke Kuroda, Hideya Sakakibara, Yasushi Yumura, Etsuko Miyagi & Mariko Murase
  • Organizer: ESHRE 2021 European Society of Human Reproduction and Embryology 37th virtual annual meewting
  • Int'l Joint Research
• [Presentation] Akifumi Ijuin, Tomonari Hayama, Mizuki Yamamoto, Hiroe Ueno, Haru Hamada, Ai Miyakoshi, Mayuko Nishi, Marina Saito, Tochihara Siori, Mitsuru Komeya, Teppei Takeshima, Shinnosuke Kuroda, Hideya Sakakibara, Yasushi Yumura, Etsuko Miyagi & Mariko Murase (2021)
  • Author(s): High Mitochondrial DNA replication in embryos derived from Myotonic dystrophy 1 female.
  • Organizer: ASRM2021 77th American society for reproductive medicine, virtual congress, Baltimore
  • Int'l Joint Research
• [Presentation] Inappropriate Reprogramming Factors Induce Sequential Ovarian Tumor Development in Rodent Ovary; Serous Cystadenoma- Benign Teratoma-Embryonal Carcinoma Sequence (2020)
  • Author(s): Tomonari Hayama, Hideya Sakakibara, Etsuko Miyagi 第72回日本産科婦人科学会学術講演会、東京、2020年4月25
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Book] 生殖医療フロントラインMOOK2、受精とその障害 (2022)
  • Author(s): 葉山智工 上野寛枝
  • Total Pages: 6
  • Publisher: 中外医学社
• [Patent(Industrial Property Rights)] 妊孕性を判定するためのバイオマーカー及びそれを用いた判定方法 (2022)
  • Inventor(s): 伊集院昌郁、葉山智工ら
  • Industrial Property Rights Holder: 伊集院昌郁、葉山智工ら
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-169943
  • Filing Date: 2022
• [Patent(Industrial Property Rights)] 妊孕性を判定するためのバイオマーカー及びそれを用いた判定方法 (2021)
  • Inventor(s): 宮城悦子、葉山智工ら
  • Industrial Property Rights Holder: 宮城悦子、葉山智工ら
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Acquisition Date: 2022
  • Overseas