The role of adipocyte-derived hormones/extracellular vesicles on bone-metastasized cancer

• Project/Area Number: 20K09422
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Kanagawa Cancer Center Research Institute
• Principal Investigator: Sato Shinya 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), 臨床研究所, 医長・室長 (30464564)
• Co-Investigator(Kenkyū-buntansha): 比留間 徹 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), その他部局等, 部長 (20254188) ; 星野 大輔 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), その他部局等, 部長代理 (30571434) ; 鷲見 公太 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), その他部局等, 医師 (30716733)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: adipo-oncology / 腫瘍関連脂肪細胞 / がん微小環境 / 骨転移 / 治療抵抗性 / 腫瘍免疫 / AI解析 / 骨髄脂肪細胞 / 脂肪細胞 / アディポカイン / 動物モデル / 分化誘導 / 癌微小環境 / がん-間質相互作用 / エクソソーム / マウス転移モデル / ホルモン / がん

Outline of Research at the Start

がんの骨転移は、骨痛や病的骨折を来し、患者さんのQOLを低下させる。骨転移したがんの治療のため、がんが骨内で増える仕組みを明らかにすることが重要である。
骨の中には脂肪細胞が豊富に存在するが、骨転移したがんに対する役割は明らかでない。本研究は、骨内の脂肪細胞の骨転移がんに対する役割の解明を目的とする。
目的を達成するため、①骨内の脂肪が増えると骨転移の頻度も増えるか②骨内の脂肪細胞が分泌する因子が、がん細胞を増やすか③骨転移したがん患者さんの骨内の脂肪細胞がどのような因子を分泌しているか、を検討する。本研究により、骨内の脂肪細胞を標的とした新規骨転移治療法につながる研究成果を得る事を目指す。

Outline of Final Research Achievements

In this study, we conducted a fundamental study to determine the role of adipocytes in cancer progression in bone metastases. First, AI analysis of pathology images containing cancer and adipose tissue showed that adipocytes-containing tissues are important for the presence of cancer. Next, histopathological analysis of 144 patients with bone metastases was performed. The results showed that in the invasive fronts of bone metastases, the presence of bone marrow adipocytes increased the density of cancer-associated fibroblasts and decreased the density of CD8-positive lymphocytes. Cancer metastasized to the adipocyte-rich marrow had increased expression of genes related to tumor immune evasion and drug treatment resistance compared to the primary cancer. These results are reported in the papers. To obtain MOA for these findings, we established cell and animal experimental systems for investigating the role of adipocyte secretion factors in cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究において、骨転移巣において脂肪細胞が局所における癌の進展に寄与する可能性を示すことができた。また、そのメカニズムとして腫瘍免疫回避、腫瘍関連線維芽細胞の誘導が起きている可能性が示唆された。本研究結果は、脂肪細胞およびその分泌因子をがんの治療標的として認識する必要性を明らかにした点で学術的意義・社会的意義がある。

Research Products

• [Journal Article] Bone marrow adipocytes induce cancer‐associated fibroblasts and immune evasion, enhancing invasion and drug resistance (2023)
  • Author(s): Sato Shinya、Hiruma Toru、Koizumi Mitsuyuki、Yoshihara Mitsuyo、Nakamura Yoshiyasu、Tadokoro Hiroko、Motomatsu Sadako、Yamanaka Takashi、Washimi Kota、Okubo Yoichiro、Yoshioka Emi、Kasajima Rika、Yamashita Toshinari、Kishida Takeshi、Yokose Tomoyuki、Miyagi Yohei
  • Journal Title: Cancer Science Volume: - Issue: 6 Pages: 2674-2688
  • DOI: 10.1111/cas.15786
  • Peer Reviewed / Open Access
• [Journal Article] Cancer cell-derived CD69 induced under lipid and oxygen starvation promotes ovarian cancer progression through fibronectin (2023)
  • Author(s): Koizume S, Kanayama T, Kimura Y, Hirano H, Takahashi T, Ota Y, Miyazaki K, Yoshihara M, Nakamura Y, Yokose T, Kato H, Takenaka K, Sato S, Tadokoro H, Miyagi E, Miyagi Y.
  • Journal Title: Cancer Sci Volume: 00 Issue: 6 Pages: 1-14
  • DOI: 10.1111/cas.15774
  • Peer Reviewed / Open Access
• [Journal Article] Histological markers, sickle-shaped blood vessels, myxoid area, and infiltrating growth pattern help stratify the prognosis of patients with myxofibrosarcoma/undifferentiated sarcoma (2023)
  • Author(s): Washimi Kota、Kasajima Rika、Shimizu Eigo、Sato Shinya、Okubo Yoichiro、Yoshioka Emi、Narimatsu Hiroto、Hiruma Toru、Katayama Kotoe、Yamaguchi Rui、Yamaguchi Kiyoshi、Furukawa Yoichi、Miyano Satoru、Imoto Seiya、Yokose Tomoyuki、Miyagi Yohei
  • Journal Title: Scientific Reports Volume: 13 Issue: 1
  • DOI: 10.1038/s41598-023-34026-w
  • Peer Reviewed / Open Access
• [Journal Article] A practical spatial analysis method for elucidating the biological mechanisms of cancers with abdominal dissemination in vivo (2022)
  • Author(s): Ota Yukihide、Sato Shinya、Yoshihara Mitsuyo、Nakamura Yoshiyasu、Miyagi Etsuko、Miyagi Yohei
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 20303-20303
  • DOI: 10.1038/s41598-022-24827-w
  • Peer Reviewed / Open Access
• [Journal Article] Chronological Change in EPHA2 Protein Expression Is Associated With Recurrence of Bladder Cancer (2022)
  • Author(s): KOIZUMI MITSUYUKI、SATO SHINYA、YOSHIHARA MITSUYO、NAKAMURA YOSHIYASU、TERAO HIDEYUKI、OKUBO YOICHIRO、WASHIMI KOTA、YOSHIOKA EMI、YOKOSE TOMOYUKI、KISHIDA TAKESHI、KOSHIKAWA NAOHIKO、MIYAGI YOHEI
  • Journal Title: Anticancer Research Volume: 42 Issue: 12 Pages: 5783-5794
  • DOI: 10.21873/anticanres.16085
  • Peer Reviewed
• [Journal Article] TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma (2022)
  • Author(s): Toda Soji、Sato Shinya、Saito Nao、Sekihara Kazumasa、Matsui Ai、Murayama Daisuke、Nakayama Hirotaka、Suganuma Nobuyasu、Okubo Yoichiro、Hayashi Hiroyuki、Iwasaki Hiroyuki、Miyagi Yohei、Hoshino Daisuke
  • Journal Title: Cancers Volume: 14 Issue: 3 Pages: 579-579
  • DOI: 10.3390/cancers14030579
  • Peer Reviewed / Open Access
• [Journal Article] Lipophagy-ICAM-1 pathway associated with fatty acid and oxygen deficiencies is involved in poor prognoses of ovarian clear cell carcinoma (2022)
  • Author(s): Koizume S, Takahashi T, Nakamura Y, Yoshihara M, Ota Y, Sato S, Tadokoro H, Yokose T, Kato H, Miyagi E, Miyagi Y
  • Journal Title: Br J Cancer Volume: ー Issue: 3 Pages: 462-473
  • DOI: 10.1038/s41416-022-01808-4
  • Peer Reviewed / Open Access
• [Journal Article] Differential diagnosis of lipoma and atypical lipomatous tumor/well‐differentiated liposarcoma by cytological analysis (2022)
  • Author(s): Sugiyama Kana、Washimi Kota、Sato Shinya、Hiruma Toru、Sakai Mai、Okubo Yoichiro、Miyagi Yohei、Yokose Tomoyuki
  • Journal Title: Diagnostic Cytopathology Volume: 50 Issue: 3 Pages: 112-122
  • DOI: 10.1002/dc.24928
  • Peer Reviewed / Open Access
• [Journal Article] Multiple cancer type classification by small RNA expression profiles with plasma samples from multiple facilities (2022)
  • Author(s): Suzuki K, Igata H, Abe M, Yamamoto Y; small RNA based cancer classification project.
  • Journal Title: Cancer Science Volume: - Issue: 6 Pages: 2144-2166
  • DOI: 10.1111/cas.15309
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic significance of reassessment of prostate biopsy specimens by experienced urological pathologists at a high-volume institution (2022)
  • Author(s): Okubo Yoichiro、Yamamoto Yayoi、Sato Shinya、Yoshioka Emi、Suzuki Masaki、Washimi Kota、Osaka Kimito、Suzuki Takahisa、Yokose Tomoyuki、Kishida Takeshi、Miyagi Yohei
  • Journal Title: Virchows Archiv Volume: - Issue: 5 Pages: 979-987
  • DOI: 10.1007/s00428-022-03272-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Machine learning-based image analysis for accelerating the diagnosis of complicated preneoplastic and neoplastic ductal lesions in breast biopsy tissues (2021)
  • Author(s): Shinya Sato , Satoshi Maki, Takashi Yamanaka, Daisuke Hoshino, Yukihide Ota, Emi Yoshioka, Kae Kawachi, Kota Washimi, Masaki Suzuki, Yoichiro Ohkubo, Tomoyuki Yokose, Toshinari Yamashita, Seiji Ohtori, Yohei Miyagi
  • Journal Title: Breast Cancer Research and Treatment Volume: online ahead of print Issue: 3 Pages: 649-659
  • DOI: 10.1007/s10549-021-06243-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinicopathological Analysis of the ISUP Grade Group And Other Parameters in Prostate Cancer: Elucidation of Mutual Impact of the Various Parameters (2021)
  • Author(s): Okubo Yoichiro、Sato Shinya、Osaka Kimito、Yamamoto Yayoi、Suzuki Takahisa、Ida Arika、Yoshioka Emi、Suzuki Masaki、Washimi Kota、Yokose Tomoyuki、Kishida Takeshi、Miyagi Yohei
  • Journal Title: Frontiers in Oncology Volume: 11
  • DOI: 10.3389/fonc.2021.695251
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component (2021)
  • Author(s): Masaki Suzuki, Rika Kasajima, Tomoyuki Yokose, Hiroyuki Ito, Eigo Shimizu, Seira Hatakeyama, Kazuaki Yokoyama, Rui Yamaguchi, Yoichi Furukawa, Satoru Miyano, Seiya Imoto, Emi Yoshioka, Kota Washimi, Yoichiro Okubo, Kae Kawachi, Shinya Sato, Yohei Miyagi
  • Journal Title: Translational Lung Cancer Research Volume: 10 Issue: 3 Pages: 1292-1304
  • DOI: 10.21037/tlcr-20-1158
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tissue factor pathway inhibitor 2 is specifically expressed in ovarian clear cell carcinoma tissues in the nucleus, cytoplasm and extracellular matrix (2021)
  • Author(s): Yukihide Ota, Shiro Koizume, Yoshiyasu Nakamura, Mitsuyo Yoshihara, Tomoko Takahashi, Shinya Sato, Shohei Myoba, Norihisa Ohtake, Hisamori Kato, Tomoyuki Yokose, Etsuko Miyagi, Yohei Miyagi
  • Journal Title: Oncology Reports Volume: 45 Issue: 3 Pages: 1023-1032
  • DOI: 10.3892/or.2021.7944
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 骨髄脂肪細胞は転移がんの浸潤・免疫回避・治療抵抗性に有利な骨微小環境を形成する (2023)
  • Author(s): 佐藤慎哉、宮城洋平
  • Organizer: 第112回日本病理学会総会
• [Presentation] 骨髄脂肪細胞の増加による 骨転移がん浸潤様式の変化 (2022)
  • Author(s): 佐藤慎哉
  • Organizer: 第42回日本肥満学会・第39回日本肥満症治療学会学術集会
• [Presentation] 脂肪細胞が、転移がんの増殖浸潤と腫瘍免疫環境に与える影響の組織学的解明 (2022)
  • Author(s): 佐藤慎哉
  • Organizer: 第43回日本肥満学会・第40回日本肥満症治療学会学術集会
• [Presentation] 骨髄脂肪細胞が骨転移がんに 与える影響の病理組織学的解析 (2022)
  • Author(s): 佐藤慎哉、宮城洋平
  • Organizer: 第111回日本病理学会総会
• [Presentation] Elucidating the role of adipocytes on bone metastasis progression through detailed pathological analysis (2022)
  • Author(s): Shinya Sato, Yoshiyasu Nakamura, and Yohei Miyagi
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] 骨髄脂肪細胞の増加による 骨転移がん浸潤様式の変化 (2022)
  • Author(s): 佐藤慎哉
  • Organizer: 第42回日本肥満学会・第39回日本肥満治療学会総会
• [Presentation] 泌尿器科腫瘍由来骨転移巣における間質浸潤様式の病理組織学的解析 (2021)
  • Author(s): 佐藤慎哉、大久保陽一郎、宮城洋平
  • Organizer: 第7回日本泌尿器腫瘍学会学術集会
• [Presentation] Regulation of host cells in metastatic organs: A Key approach to develop new therapies for metastatic cancer (2021)
  • Author(s): 佐藤慎哉、宮城洋平
  • Organizer: 第80回日本癌学会総会
• [Presentation] 乳腺生検組織における複雑な良性・悪性乳管内病変のAI画像解析システム開発 (2021)
  • Author(s): 佐藤慎哉、牧聡、宮城洋平
  • Organizer: 第110回日本病理学会総会
• [Presentation] AI-mediated image analysis of preneoplastic/neoplastic ductal lesion in breast biopsy tissues (2021)
  • Author(s): Shinya Sato, Satoshi Maki, and Yohei Miyagi
  • Organizer: 第110回日本病理学会総会
• [Presentation] HNSCC SEVs drive tumor angiogenesis via ephrin reverse signaling (2020)
  • Author(s): Shinya Sato and Yohei Miyagi
  • Organizer: 第79回日本癌学会総会