Functional analysis of CD109 in tumor progression using osteosarcoma cells and tissue

• Project/Area Number: 19K07503
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Nagoya University
• Principal Investigator: Mii Shinji 名古屋大学, 医学系研究科, 准教授 (80646505)
• Co-Investigator(Kenkyū-buntansha): 高橋 雅英 藤田医科大学, その他部局等, 教授 (40183446)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CD109 / 骨肉腫 / TGF-β / BMP / 骨芽細胞 / 間葉系幹細胞 / 病理学 / 希少がん

Outline of Research at the Start

細胞表面に存在するタンパク質であるCD109は，様々な悪性腫瘍で増加しており，腫瘍の発症あるいは進行を助長するため注目されているが，なぜそのような機能を持つか，詳細は不明である．
これまでに，骨肉腫に由来する培養細胞でCD109タンパク質が増えており，それを人工的に減らすことで，細胞の悪性度が下がるという実験結果が得られている．
そこで，骨肉腫を対象とすることで，CD109タンパク質の機能を調べるとともに，新たな治療標的となりうるかについても検討する．

Outline of Final Research Achievements

In this study, we investigated the role of CD109 using osteosarcoma cell lines and human osteosarcoma tissue. We performed immunohistochemical analysis on human osteosarcoma tissue and found that patients with CD109-high osteosarcoma had a significantly worse prognosis than those with CD109-low one.
Although no significant difference was found in TGF-β1 signaling between CD109-knockdown osteosarcoma cells and control cells, we observed that CD109 suppressed SMAD1/5/9 phosphorylation by BMP-2, which is one of the member of TGF-β superfamily.
These results suggest that CD109 is involved in the exacerbation of osteosarcoma via not TGF-β but BMP singlaing.

Academic Significance and Societal Importance of the Research Achievements

近年，多くのがんで効果的な治療法が登場しているにも関わらず，難治性の希少がんである骨肉腫においては依然として新規治療法の開発が進んでいない．本研究では，CD109の発現が高い骨肉腫症例が，CD109の発現が低い症例に比べて有意に予後不良であり，その原因の1つがCD109による影響であることを示す成果が得られており，CD109を標的とした骨肉腫の新規治療法の開発につながる可能性がある．

Research Products

• [Journal Article] Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics. (2022)
  • Author(s): Iida T, Mizutani Y, Esaki N, Ponik SM, Burkel BM, Weng L, Kuwata K, Masamune A, Ishihara S, Haga H, Kataoka K, Mii S, Shiraki Y, Ishikawa T, Ohno E, Kawashima H, Hirooka Y, Fujishiro M, Takahashi M, Enomoto A.
  • Journal Title: Oncogene. Volume: 41 Pages: 2764-2777
  • DOI: 10.1038/s41388-022-02288-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade. (2022)
  • Author(s): Miyai Y, Sugiyama D, Hase T, Asai N, Taki T, Nishida K, Fukui T, Chen-Yoshikawa TF, Kobayashi H, Mii S, Shiraki Y, Hasegawa Y, Nishikawa H, Ando Y, Takahashi M, Enomoto A.
  • Journal Title: Life Sci Alliance. Volume: 5 Pages: e202101230
  • DOI: 10.26508/lsa.202101230
  • Peer Reviewed / Open Access
• [Journal Article] Matrix remodeling-associated protein 8 is a marker of a subset of cancer-associated fibroblasts in pancreatic cancer. (2022)
  • Author(s): Ichihara R, Shiraki Y, Mizutani Y, Iida T, Miyai Y, Esaki N, Kato A, Mii S, Ando R, Hayashi M, Takami H, Fujii T, Takahashi M, Enomoto A.
  • Journal Title: Pathol Int. Volume: 72 Pages: 161-175
  • DOI: 10.1111/pin.13198
  • Peer Reviewed / Open Access
• [Journal Article] Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity. (2021)
  • Author(s): Hara A, Kato K, Ishihara T, Kobayashi H, Asai N, Mii S, Shiraki Y, Miyai Y, Ando R, Mizutani Y, Iida T, Takefuji M, Murohara T, Takahashi M, Enomoto A.
  • Journal Title: Genes Cells. Volume: 26 Pages: 495-512
  • DOI: 10.1111/gtc.12855
  • Peer Reviewed / Open Access
• [Journal Article] Detection of serum/salivary exosomal Alix in patients with oral squamous cell carcinoma. (2021)
  • Author(s): Nakamichi E, Sakakura H, Mii S, Yamamoto N, Hibi H, Asai M, Takahashi M.
  • Journal Title: Oral Dis. Volume: 27 Pages: 439-447
  • DOI: 10.1111/odi.13565
  • Peer Reviewed
• [Journal Article] The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. (2021)
  • Author(s): Kobayashi H, Gieniec KA, Wright JA, Wang T, Asai N, Mizutani Y, Iida T, Ando R, Suzuki N, Lannagan TR, Ng JQ, Hara A, Shiraki Y, Mii S (14番目/36人中), ..., Enomoto A, Takahashi M, Worthley DL, Woods SL.
  • Journal Title: Gastroenterology. Volume: 160 Pages: 1224-1239.e30
  • DOI: 10.1053/j.gastro.2020.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. (2020)
  • Author(s): Taki T, Shiraki Y, Enomoto A, Weng L, Chen C, Asai N, Murakumo Y, Yokoi K, Takahashi M, Mii S.
  • Journal Title: Cancer Sci. Volume: 111 Pages: 4616-4628
  • DOI: 10.1111/cas.14673
  • Peer Reviewed / Open Access
• [Journal Article] Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells. (2020)
  • Author(s): Chen C, Enomoto A, Weng L, Taki T, Shiraki Y, Mii S, Ichihara R, Kanda M, Koike M, Kodera Y, Takahashi M.
  • Journal Title: Cancer Sci. Volume: 111 Pages: 4303-4317
  • DOI: 10.1111/cas.14637
  • Peer Reviewed / Open Access
• [Journal Article] The Daple-CK1ε complex regulates Dvl2 phosphorylation and canonical Wnt signaling. (2020)
  • Author(s): Esaki N, Enomoto A, Takagishi M, Mizutani Y, Iida T, Ushida K, Shiraki Y, Mii S, Takahashi M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 532 Pages: 406-413
  • DOI: 10.1016/j.bbrc.2020.08.066
  • Peer Reviewed
• [Journal Article] Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma. (2020)
  • Author(s): Ohara Y, Enomoto A, Tsuyuki Y, Sato K, Iida T, Kobayashi H, Mizutani Y, Miyai Y, Hara A, Mii S, Suzuki J, Yamashita K, Ito F, Motooka Y, Misawa N, Fukui T, Kawaguchi K, Yokoi K, Toyokuni S.
  • Journal Title: Oncol Rep. Volume: 44 Pages: 838-848
  • DOI: 10.3892/or.2020.7669
  • Peer Reviewed / Open Access
• [Journal Article] The significance of molecular biomarkers on clinical survival outcome differs depending on colon cancer sidedness. (2020)
  • Author(s): Hirabayashi S, Hayashi M, Nakayama G, Mii S, Hattori N, Tanabe H, Kanda M, Tanaka C, Kobayashi D, Yamada S, Koike M, Fujiwara M, Takahashi M, Kodera Y.
  • Journal Title: Anticancer Res. Volume: 40 Pages: 201-211
  • DOI: 10.21873/anticanres.13941
  • Peer Reviewed
• [Journal Article] CD109: a multifunctional GPI-anchored protein with key roles in tumor progression and physiological homeostasis. (2019)
  • Author(s): Mii S, Enomoto A, Shiraki Y, Taki T, Murakumo Y, Takahashi M.
  • Journal Title: Pathol Int. Volume: 69 Pages: 249-259
  • DOI: 10.1111/pin.12798
  • Peer Reviewed
• [Journal Article] Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. (2019)
  • Author(s): Mizutani Y, Kobayashi H, Iida T, Asai, Masamune A, Hara A, Esaki N, Ushida K, Mii S, Shiraki Y, Ando, Weng, Ishihara, Ponik SM, Conklin MW, Haga H, Nagasaka A, Miyata T, Matsuyama M, Kobayashi T, Fujii T, Yamada S, Yamaguchi J, Wang T, Woods SL, Worthley DL, Shimamura T, Fujishiro M, Hirooka Y, Enomoto A, Takahashi M.
  • Journal Title: Cancer Res. Volume: 79 Pages: 5367-5381
  • DOI: 10.1158/0008-5472.CAN-19-0454
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 悪性腫瘍におけるGPIアンカー型膜タンパク質CD109の発現と臨床的意義 (2020)
  • Author(s): 三井 伸二，白木 之浩，滝 哲郎，榎本 篤，高橋 雅英
  • Organizer: 第109回日本病理学会総会
• [Presentation] 肺腺癌における癌関連タンパク質CD109の機能解析 (2020)
  • Author(s): 滝 哲郎，三井 伸二，白木 之浩，榎本 篤，高橋 雅英
  • Organizer: 第109回日本病理学会総会
• [Presentation] CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling (2020)
  • Author(s): 三井 伸二，滝 哲郎，白木 之浩，榎本 篤，高橋 雅英
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 骨組織および骨肉腫におけるGPIアンカー型膜タンパク質CD109の発現とその意義 (2019)
  • Author(s): 三井 伸二，白木 之浩，下山 芳江，榎本 篤，髙橋 雅英
  • Organizer: 第108回日本病理学会総会
• [Presentation] 肺腺癌における癌関連タンパク質CD109の機能解析 (2019)
  • Author(s): 滝 哲郎，三井 伸二，白木 之浩，榎本 篤，高橋 雅英
  • Organizer: 第108回日本病理学会総会
• [Presentation] 骨肉腫におけるGPIアンカー型膜タンパク質CD109の発現とその意義 (2019)
  • Author(s): 三井 伸二，白木 之浩，滝 哲郎，榎本 篤，髙橋 雅英
  • Organizer: 第16回日本病理学会カンファレンス
• [Presentation] 肺腺癌におけるGPIアンカー型膜タンパク質CD109の機能解析 (2019)
  • Author(s): 滝 哲郎，三井 伸二，白木 之浩，榎本 篤，高橋 雅英
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Exosome-associated protein Alix as a novel diagnostic marker for oral squamous cell carcinoma (2019)
  • Author(s): Eiji Nakamichi, Masato Asai, Hiroki Sakakura, Shinji Mii, Noriyuki Yamamoto, Hideharu Hibi, Masahide Takahashi
  • Organizer: American Society for Exosomes and Microvesicles 2019
• [Remarks] 腫瘍病理学 分子病理学分野
  • URL: https://www.med.nagoya-u.ac.jp/patho2/