Proposal of new diagnosis, treatment, prevention approach for endometrial cancer targeting estrogen-mediated pathway

• Project/Area Number: 21K09523
• 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: Kyoto Prefectural University of Medicine
• Principal Investigator: 森 泰輔 京都府立医科大学, 医学(系)研究科(研究院), 教授 (00569824)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 子宮体癌 / エストロゲン受容体 / バイオマーカー

Outline of Research at the Start

本研究では、① ERRがエストロゲン応答や薬剤感受性に及ぼす影響、② ERRとがんの代謝異常との関連性、について明らかにすることで、個別化医療実現のための新規診断バイオマーカー開発や新たな治療および疾患予防アプローチを発案する。

Outline of Annual Research Achievements

子宮内膜に限局する病変に対して妊孕能温存療法としてプロゲスチン療法が行われているが、その再発率は高い。このように子宮体癌に対する新たな治療法の開発が切望されている。子宮体癌に対してこれまで多くの分子標的薬が試行されてきたが、いずれも満足な結果は得られていない。網羅的遺伝子解析から子宮体癌は単一の強いがん遺伝子の変異では癌化しにくいことが示されており、腫瘍の生物学的特性に基づいた治療戦略が求められている。
研究代表者はこれまで一貫して「エストロゲン依存性増殖機構」に着目し研究を展開してきた中で、エストロゲン関連受容体（ERRa）が子宮体癌における細胞増殖、浸潤・転移、血管新生、アポトーシス誘導を制御し、これを標的とする化合物が in vitro および in vivo において抗腫瘍効果をもたらすことを実証してきた。本研究では、① エストロゲン関連受容体がエストロゲン応答や薬剤感受性に及ぼす影響、② エストロゲン関連受容体とがんの代謝異常との関連性、について明らかにする。
① エストロゲン応答や薬剤感受性に及ぼす影響について
ERRとエストロゲン受容体（ER）の発現レベルについて明らかな相関関係は認めなかった。ERRはERが及ぼすエストロゲン応答を抑制することが示された。またERRがエストロゲン生合成酵素発現を誘導することからエストロゲンシグナル伝達に関する作用が示唆される。
② エストロゲン関連受容体とがんの代謝異常との関連性について
メタボローム解析により化学療法抵抗性機序として、新たな因子Xを得た。Xは子宮体癌細胞で過剰発現し予後と関連する。低栄養環境におくことでプラチナ製剤への感受性に関連することも明らかにした。

Research Products

• [Journal Article] A Case Report of Occult Breast Cancer Detected by Diagnostic Laparoscopy for Suspected Ovarian Cancer (2024)
  • Author(s): Egami A, Tarumi Y, Okamura A, Aoyama K, Kataoka H, Kokabu T, Yoriki K, Ito F, Mori T.
  • Journal Title: Case Rep Obstet Gynecol Volume: 2024 Pages: 8851045-8851045
  • DOI: 10.1155/2024/8851045
  • Peer Reviewed
• [Journal Article] Dienogest does not augment the gene expression of adhesion molecules, MCP-1, and monocyte adherence in human endothelial cells (2023)
  • Author(s): Tahara N, Ito F, Kawamata M, Otani M, Mori T.
  • Journal Title: Gynecological Endocrinology Volume: 40 Issue: 1 Pages: 2270621-2270621
  • DOI: 10.1080/09513590.2023.2270621
  • Peer Reviewed
• [Journal Article] Decrease in activated regulatory T cell populations in the endometrium during ovulation in endometriosis (2023)
  • Author(s): Fujii M, Tanaka Y, Okimura H, Maeda E, Hamaguchi M, Fukui M, Kitawaki J, Mori T.
  • Journal Title: J Reprod Immunol. Volume: 156 Pages: 103825-103825
  • DOI: 10.1016/j.jri.2023.103825
  • Peer Reviewed
• [Journal Article] Low-Nutrient Environment-Induced Changes in Inflammation, Cell Proliferation, and PGC-1α Expression in Stromal Cells with Ovarian Endometriosis (2023)
  • Author(s): Shimura K, Tarumi Y, Fujii M, Ogawa K, Maeda E, Tanaka Y, Okimura H, Kataoka H, Takaoka O, Ito F, Koshiba A, Khan KN, Kusuki I, Kitawaki J, Mori T.
  • Journal Title: Reprod Sci. Volume: 30 Issue: 4 Pages: 1094-1102
  • DOI: 10.1007/s43032-022-01089-5
  • Peer Reviewed / Open Access
• [Journal Article] Successful resection of growing teratoma syndrome in the abdominal wall with reconstruction using tensor fascia lata muscle flap: A case report and literature review (2023)
  • Author(s): Miho Iwai, Kaori Yoriki, Kohei Aoyama, Yosuke Tarumi, Hisashi Kataoka, Tetsuya Kokabu, Toshiaki Numajiri, Taisuke Mori
  • Journal Title: Gynecologic Oncology Reports Volume: 46 Pages: 101161-101161
  • DOI: 10.1016/j.gore.2023.101161
  • Peer Reviewed / Open Access
• [Journal Article] Computed tomography, magnetic resonance imaging, and positron emission tomography/computed tomography findings for the diagnosis of malignant struma ovarii: A case report (2023)
  • Author(s): Yamauchi Saiko、Kokabu Tetsuya、Kataoka Hisashi、Yoriki Kaori、Takahata Akiko、Mori Taisuke
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 49 Issue: 5 Pages: 1456-1461
  • DOI: 10.1111/jog.15619
  • Peer Reviewed
• [Journal Article] he Tpl2-MEK pathway plays a critical role in spheroid-cultured endometriotic stromal cells (2023)
  • Author(s): Minami T, Tsuzuki Y, Tanaka Y, Kitawaki J, Mori T.
  • Journal Title: Am J Reprod Immunol . Volume: 89 Issue: 5
  • DOI: 10.1111/aji.13689
  • Peer Reviewed
• [Journal Article] Postoperative Pregnancy Outcomes Following Laparoscopic Surgical Management in Women with Stage III/IV Endometriosis: A Single-Center Follow-Up Study (2023)
  • Author(s): Fujii M, Koshiba A, Ito F, Kusuki I, Kitawaki J, Mori T.
  • Journal Title: Gynecol Minim Invasive Ther Volume: 12 Issue: 3 Pages: 153-160
  • DOI: 10.4103/gmit.gmit_132_22
  • Peer Reviewed
• [Journal Article] Hepcidin as a key regulator of iron homeostasis triggers inflammatory features in the normal endometrium (2023)
  • Author(s): Izumi Yuko、Kataoka Hisashi、Koshiba Akemi、Ito Fumitake、Tanaka Yukiko、Takaoka Osamu、Maeda Eiko、Okimura Hiroyuki、Sugahara Takuya、Tarumi Yosuke、Shimura Koki、Khan Khaleque N.、Kusuki Izumi、Mori Taisuke
  • Journal Title: Free Radical Biology and Medicine Volume: 209 Pages: 191-201
  • DOI: 10.1016/j.freeradbiomed.2023.10.402
  • Peer Reviewed / Open Access
• [Journal Article] Association between tissue stress reaction and ACE2/TMPRSS2 expression in endometria of reproductive aged women before and during Covid-19 pandemic (2023)
  • Author(s): Ogawa K, Khan KN, Fujishita A, Kitawaki J, Mori T.
  • Journal Title: BMC Women’s Health Volume: 23 Issue: 1 Pages: 229-238
  • DOI: 10.1186/s12905-023-02378-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Is neonatal uterine bleeding responsible for early-onset endometriosis? (2023)
  • Author(s): Ogawa Kanae、Khan Khaleque N、Kuroboshi Haruo、Koshiba Akemi、Shimura Koki、Tajiri Tatsuro、Fumino Shigehisa、Fujita Hiroyuki、Okubo Tomoharu、Fujiwara Yoichiro、Horiguchi Go、Teramukai Satoshi、Fujishita Akira、Itoh Kyoko、Guo Sun-Wei、Kitawaki Jo、Mori Taisuke
  • Journal Title: Reproductive Biology and Endocrinology Volume: 21 Issue: 1 Pages: 56-65
  • DOI: 10.1186/s12958-023-01099-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathogenesis of human adenomyosis: current understanding and its association with infertility (2022)
  • Author(s): Khan KN, Fujishita A, Mori T
  • Journal Title: J Clin Med. Volume: 11 Issue: 14 Pages: 4057-4086
  • DOI: 10.3390/jcm11144057
  • Peer Reviewed / Open Access
• [Journal Article] Clinical practice guidelines for endometriosis in Japan (The 3rd edition). (2022)
  • Author(s): Harada T, Taniguchi F, Kitajima M, Kitawaki J, Koga K, Momoeda M, Mori T, Murakami T, Narahara H, Osuga Y, Yamaguchi K.
  • Journal Title: J Obstet Gynaecol Res Volume: 48 Issue: 12 Pages: 2993-3044
  • DOI: 10.1111/jog.15416
  • Peer Reviewed / Open Access
• [Journal Article] Reduced innate lymphoid cells in the endometrium of women with endometriosis (2022)
  • Author(s): Takuya Sugahara, Yukiko Tanaka, Masahide Hamaguchi, Maya Fujii, Koki Shimura, Kanae Ogawa, Taisuke Mori, Izumi Kusuki, Michiaki Fukui, Jo Kitawaki
  • Journal Title: Am J Reprod Immunol . Volume: 87 Issue: 1
  • DOI: 10.1111/aji.13502
  • Peer Reviewed
• [Journal Article] 3D-Image-Guided Multi-Catheter Interstitial Brachytherapy for Bulky and High-Risk Stage IIB-IVB Cervical Cancer (2022)
  • Author(s): Kokabu T, Masui K, Tarumi Y, Noguchi N, Aoyama K, Kataoka H, Matsushima H, Yoriki K, Simizu D, Yamazaki H, Yamada K, Mori T
  • Journal Title: Cancers Volume: 14(5) Issue: 5 Pages: 1257-1257
  • DOI: 10.3390/cancers14051257
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Robot-assisted laparoscopic hysterectomy for early-stage endometrial cancer with massive uterine leiomyomas: A case report (2022)
  • Author(s): Kakibuchi A, Ito F, Kokabu T, Okimura H, Takaoka O, Mori T.
  • Journal Title: Int J Surg Case Rep Volume: 97 Pages: 107473-107473
  • DOI: 10.1016/j.ijscr.2022.107473
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone Receptor Status of Epithelial Cells as a Predictive Marker for Postoperative Recurrence of Endometriosis (2022)
  • Author(s): Tarumi Y, Mori T, Shimura K, Izumi Y, Okimura H, Kataoka H, Kokabu T, Ito F, Koshiba A, Khan KN, Kusuki I, Kitawaki J.
  • Journal Title: J Clin Endocrinol Metab. Volume: 107 Issue: 6 Pages: 1552-1559
  • DOI: 10.1210/clinem/dgac118
  • Peer Reviewed
• [Journal Article] Changes in the proportion of regulatory T cell subpopulations during menstrual cycle and early pregnancy (2022)
  • Author(s): Okimura H, Tanaka Y, Fujii M, Shimura K, Maeda E, Ito F, Khan KN, Nakamura Y, Mori T, Kitawaki J.
  • Journal Title: Am J Reprod Immunol. Volume: 88 Issue: 6
  • DOI: 10.1111/aji.13636
  • Peer Reviewed
• [Journal Article] Oncologic outcomes in elderly patients who underwent hysterectomy for endometrial cancer: a multi-institutional survey in Kinki District, Japan (2022)
  • Author(s): Tanaka Tomohito、Matsumura Noriomi、et al.
  • Journal Title: International Journal of Clinical Oncology Volume: - Issue: 6 Pages: 1084-1092
  • DOI: 10.1007/s10147-022-02152-6
  • Peer Reviewed / Open Access
• [Journal Article] Successful nedaplatin desensitization therapy in a patient with platinum-sensitive recurrent ovarian cancer: A case report and literature review (2022)
  • Author(s): Kokabu T, Aoyama K, Tarumi Y, Kataoka H, Yoriki K, Mori T.
  • Journal Title: Gynecol Oncol Rep. Volume: 43 Pages: 101065-101065
  • DOI: 10.1016/j.gore.2022.101065
  • Peer Reviewed / Open Access
• [Journal Article] Genistein induces long-term expression of progesterone receptor regardless of estrogen receptor status and improves the prognosis of endometrial cancer patients (2022)
  • Author(s): Yoriki K, Mori T, Aoyama K, Tarumi Y, Kataoka H, Kokabu T, Kitawaki J.
  • Journal Title: Sci Rep Volume: 12 Issue: 1 Pages: 10303-10303
  • DOI: 10.1038/s41598-022-13842-6
  • Peer Reviewed / Open Access
• [Journal Article] A targeted educational program improves the fundamental knowledge on menstrual pain and endometriosis in young women: The Endometriosis Awareness Promotion Project (2022)
  • Author(s): Khan KN, Ogawa K, Iwasa K, Kuroboshi H, Okimura H, Koshiba A et al.
  • Journal Title: Reprod Biomed Online Volume: 45(6) Issue: 6 Pages: 1216-1229
  • DOI: 10.1016/j.rbmo.2022.07.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased occurrence of endometriosis in women with Chlamydia trachomatis infection (2021)
  • Author(s): Khan Khaleque N.、Fujishita Akira、Kitajima Michio、Ishimaru Tadayuki、Ogawa Kanae、Koshiba Akemi、Mori Taisuke、Kitawaki Jo
  • Journal Title: American Journal of Reproductive Immunology Volume: 86 Issue: 6 Pages: 13498-13503
  • DOI: 10.1111/aji.13498
  • Peer Reviewed / Open Access
• [Journal Article] Primary ovarian leiomyoma associated with multiple uterine leiomyomas (2021)
  • Author(s): Ito Fumitake、Kitamura Yoshihiro、Kokabu Tetsuya、Mori Taisuke、Kusuki Izumi、Kitawaki Jo
  • Journal Title: Gynecology and Minimally Invasive Therapy Volume: 10 Issue: 1 Pages: 50-50
  • DOI: 10.4103/gmit.gmit_97_19
  • Peer Reviewed / Open Access
• [Journal Article] An axonemal alteration in apical endometria of human adenomyosis (2021)
  • Author(s): Khan KN, Fujishita A, Suematsu T, Ogawa K, Koshiba A, Mori T, Itoh K, Teramukai S, Matsuda K, Nakashima M, Kitawaki J
  • Journal Title: Hum Reprod Volume: 36(6) Issue: 6 Pages: 1574-1589
  • DOI: 10.1093/humrep/deab090
  • Peer Reviewed
• [Journal Article] Levofloxacin or GnRHa treatment decreases intrauterine microbial colonization in human endometriosis (2021)
  • Author(s): Khan KN, Fujishita A, Muto H, Masumoto H, Ogawa K, Koshiba A, Mori T, Itoh K, Teramukai S, Matsuda K, Nakashima M, Kitawaki J.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. Volume: 264 Pages: 103-116
  • DOI: 10.1016/j.ejogrb.2021.07.014
  • Peer Reviewed
• [Journal Article] Severe coronavirus disease pneumonia in a pregnant woman at 25 weeks' gestation: A case report (2021)
  • Author(s): Waratani Miyoko、Ito Fumitake、Tanaka Yukiko、Mabuchi Aki、Mori Taisuke、Kitawaki Jo
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 47 Issue: 4 Pages: 1583-1588
  • DOI: 10.1111/jog.14701
  • Peer Reviewed
• [Journal Article] Interleukin‐9 produced by helper T cells stimulates interleukin‐8 expression in endometriosis (2020)
  • Author(s): Tarumi Yosuke、Mori Taisuke、Okimura Hiroyuki、Maeda Eiko、Tanaka Yukiko、Kataoka Hisashi、Ito Fumitake、Koshiba Akemi、Kusuki Izumi、Kitawaki Jo
  • Journal Title: American Journal of Reproductive Immunology Volume: - Issue: 3
  • DOI: 10.1111/aji.13380
  • Peer Reviewed / Int'l Joint Research