Analysis on the role of CEACAM1 in human mastocytosis

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K08362
• Research Institution: Kyoto University
• Principal Investigator: 片岡 竜貴 京都大学, 医学研究科, 講師 (20343254)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: マスト細胞 / 甲状腺髄様癌 / CEACAM1 / SHP-1 / Src family kinases

Outline of Annual Research Achievements

マストサイトーシス（色素性蕁麻疹）はKIT遺伝子に機能獲得性変異が生じマスト細胞が腫瘍性増殖することで引き起こされる。この疾患のヒトでの発生頻度は低いが、アナフィラキシーショックを起こしやすく治療が必要である。しかしながら現時点では対症療法しか存在せず根治療法は存在しない。
本研究において、我々のグループはヒトマストサイトーシス臨床サンプル・細胞株に表面抗原CEACAM1-Lが発現すること、CEACAM1-Lが脱リン酸化酵素SHP-1を活性化しこの細胞の変異型KIT依存性の増殖を抑制することを見出した。これはCEACAM1-Lがヒトマストサイトーシスの治療標的となり得ることを示す結果であり、現在開発中のCEACAM1-Lに対する抗体療法（ハーバード大・Blumberg RS教授ら）の応用が期待された。
同時に、我々はヒト甲状腺髄様癌臨床サンプル・細胞株にも表面抗原CEACAM1-Lが発現すること、CEACAM1-Lがリン酸化酵素Src family kinases (SFKs) を活性化しこの細胞の変異型RET依存性の増殖を抑制することも見出した。CEACAM1-Lは、表面抗原CEACAM1のアイソフォームの1つであり、構造からは抑制性シグナルを伝達し細胞増殖を負に制御することが予想されたが、ある種の腫瘍ではCEACAM-Lの発現が増殖能促進と正に相関するなど予想と反する観察も多く為されてきた。我々の今回の実績は、こうした乖離を分子生物学的に説明しうるものであり、現在開発中の抗CEACAM1療法の臨床応用の副作用を予想する上で重要な知見と考える。

Research Products

• [Journal Article] Angiolymphoid hyperplasia with eosinophilia: A case of spontaneous partial regression post-biopsy. (2018)
  • Author(s): Cho M, Kaku Y, Goto K, Endo Y, Kataoka T, Otsuka A, Kabashima K.
  • Journal Title: J Dermatol Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed
• [Journal Article] Mast Cells Exhibiting Strong Cytoplasmic Staining for IgE and High Affinity IgE Receptor are Increased in IgG4-Related Disease. (2018)
  • Author(s): Nishida K, Gion Y, Takeuchi M, Tanaka T, Kataoka TR, Yoshino T, Sato Y.
  • Journal Title: Sci Rep Volume: 8 Pages: 4656
  • DOI: 10.1038/s41598-018-23043-9
  • Peer Reviewed / Open Access
• [Journal Article] RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice. (2018)
  • Author(s): Morita K, Tokushige C, Maeda S, Kiyose H, Noura M, Iwai A, Yamada M, Kashiwazaki G, Taniguchi J, Bando T, Hirata M, Kataoka TR, Nakahata T, Adachi S, Sugiyama H, Kamikubo Y.
  • Journal Title: Blood Adv Volume: 2 Pages: 509-515
  • DOI: 10.1182/bloodadvances.2017009324
  • Peer Reviewed / Open Access
• [Journal Article] SLAM family member 8 is involved in oncogenic KIT-mediated signaling in human mastocytosis. (2018)
  • Author(s): Sugimoto A, Kataoka TR, Ueshima C, Takei Y, Kitamura K, Hirata M, Nomura T, Haga H.
  • Journal Title: Exp Dermatol Volume: - Pages: -
  • DOI: 10.1111/exd.13523
  • Peer Reviewed / Open Access
• [Journal Article] Total cell necrosis of metastatic malignant melanoma at the regional lymph node in a patient treatment with nivolumab. (2018)
  • Author(s): Komori T, Otsuka A, Kaku Y, Irie H, Honda T, Hirata M, Kataoka TR, Kabashima K.
  • Journal Title: J Dermatol Volume: 45 Pages: e11-e12
  • DOI: 10.1111/1346-8138.14040
  • Peer Reviewed
• [Journal Article] Angiomatoid fibrous histiocytoma of the scalp mimicking cutaneous angiosarcoma in incisional biopsy containing CD31-positive histiocytes: A potential histopathological pitfall. (2018)
  • Author(s): Kanameishi S, Kaku Y, Goto K, Ishida Y, Endo Y, Dainichi T, Sakurai T, Kataoka T, Miyagawa-Hayashino A, Kabashima K.
  • Journal Title: J Dermatol Volume: 45 Pages: 235-237
  • DOI: 10.1111/1346-8138.13843
  • Peer Reviewed
• [Journal Article] Genetic regulation of the RUNX transcription factor family has antitumor effects. (2017)
  • Author(s): Morita K, Suzuki K, Maeda S, Matsuo A, Mitsuda Y, Tokushige C, Kashiwazaki G, Taniguchi J, Maeda R, Noura M, Hirata M, Kataoka T, Yano A, Yamada Y, Kiyose H, Tokumasu M, Matsuo H, Tanaka S, Okuno Y, Muto M, Naka K, Ito K, Kitamura T, Kaneda Y, Liu PP, Bando T, Adachi S, Sugiyama H, Kamikubo Y.
  • Journal Title: J Clin Invest Volume: 127 Pages: 2815-2828
  • DOI: 10.1172/JCI91788
  • Peer Reviewed / Open Access
• [Journal Article] Killer cell immunoglobulin-like receptor 2DL4 is expressed in and suppresses the cell growth of Langerhans cell histiocytosis. (2017)
  • Author(s): Takei Y, Ueshima C, Kataoka TR, Hirata M, Sugimoto A, Rokutan-Kurata M, Moriyoshi K, Ono K, Murakami I, Iwamoto S, Haga H.
  • Journal Title: Oncotarget Volume: 8 Pages: 36964-36972
  • DOI: 10.18632/oncotarget.16936
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of neuropilin-1 on macrophages modulates antibody-mediated tumoricidal activity. (2017)
  • Author(s): Kawaguchi K, Suzuki E, Nishie M, Kii I, Kataoka TR, Hirata M, Inoue M, Pu F, Iwaisako K, Tsuda M, Yamaguchi A, Haga H, Hagiwara M, Toi M.
  • Journal Title: Cancer Immunol Immunother Volume: 66 Pages: 1131-1142
  • DOI: 10.1007/s00262-017-2002-2
  • Peer Reviewed
• [Journal Article] Maculopapular rash during a nadir period in a patient with acute myeloid leukaemia. (2017)
  • Author(s): Komori T, Kogame T, Nomura T, Kaku Y, Endo Y, Ueshima C, Hirata M, Kataoka TR, Kawabata H, Kabashima K.
  • Journal Title: Eur J Dermatol Volume: 27 Pages: 316-317
  • DOI: 10.1684/ejd.2017.2991
  • Peer Reviewed
• [Journal Article] CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells. (2017)
  • Author(s): Ueshima C, Kataoka TR, Takei Y, Hirata M, Sugimoto A, Hirokawa M, Okayama Y, Blumberg RS, Haga H.
  • Journal Title: Cancer Med Volume: 6 Pages: 845-856
  • DOI: 10.1002/cam4.1050
  • Peer Reviewed / Open Access / Int'l Joint Research