Functional analyses and developments of new therapies targeting LSD1 in gastrointestinal cancers

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16K19941
• Research Institution: Kumamoto University
• Principal Investigator: 小澄 敬祐 熊本大学, 医学部附属病院, 非常勤診療医師 (50594884)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 消化器癌 / LSD1 / がん代謝 / オートファジー / 腫瘍免疫 / 腸内細菌 / 予後予測マーカー / 炎症

Outline of Annual Research Achievements

本研究の目的は、消化器癌におけるがん代謝関連酵素Lysine Specific Demethylase-1（LSD1）の発現意義を解明する事である。LSD1の癌進展に関わる機序を解明すべく、分子病理学的因子、腸内細菌、腫瘍免疫との関連を解析した。食道癌においてPIK3CA変異は重要なGenetic changeだが、癌部のLSD1発現レベルとPIK3CA変異に相関はなかった（P=0.14）。また、がん代謝に関与するNRF2とも相関はなかった（P=0.54）。腫瘍免疫の観点から、食道癌における癌部のLSD1発現レベルとCD8陽性細胞、FOXP3陽性細胞、tumor-infiltrating lymphocytes、PD-L1発現（癌部）、IDO1発現（癌部）と関連を見たが、いずれも相関はなかった（P>0.23）。消化器癌では、LINE-1メチル化レベルは予後予測マーカーとなりうる。解析の結果、LSD1が癌部のLINE-1メチル化レベルと有意に逆相関である事を認めた。また、腫瘍免疫のperitumoral lymphocytic reactionとも有意に逆相関だった。論文執筆を検討中である。大腸癌において重要ながん関連遺伝子としてLSD1、PTGS2が挙げられ、これらは互いに影響しうる。In vitroで、PTGS2阻害剤であるアスピリンがPIK3CA変異大腸癌細胞株に有意に腫瘍抑制効果が強い事を示した（Oncotarget 2017）。また、患者の肥満度・食生活が大腸癌発癌リスクに関連する事を報告した（Eur J Epidemiol 2017、Gastroenterology 2017）。現在、大腸癌におけるPTGS2発現レベルと腫瘍免疫・予後を解析中である。また、がん代謝・腫瘍免疫に関連する腸内細菌として、大腸癌中のBifidobacteriumの存在意義を解析中である。

Research Products

• [Journal Article] Pyloroplasty may reduce weight loss 1 year after esophagectomy. (2018)
  • Author(s): Harada K, Yoshida N, Baba Y, Nakamura K, Kosumi K, Ishimoto T, Iwatsuki M, Miyamoto Y, Sakamoto Y, Ajani JA, Watanabe M, Baba H.
  • Journal Title: Dis Esophagus. Volume: Mar 1 Pages: 31(3)
  • DOI: 10.1093/dote/dox127.
  • Peer Reviewed
• [Journal Article] TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas. (2018)
  • Author(s): Hamada T, Soong TR, Masugi Y, Kosumi K*, Nowak JA, da Silva A, Mu XJ, Twombly TS, Koh H, Yang J, Song M, Liu L, Gu M, Shi Y, Nosho K, Morikawa T, Inamura K, Shukla SA, Wu CJ, Garraway LA, Zhang X, Wu K, Meyerhardt JA, Chan AT, Glickman JN, Rodig SJ, Freeman GJ, Fuchs CS, Nishihara R, Giannakis M, Ogino S.
  • Journal Title: OncoImmunology. Volume: 21 Feb Pages: Epub
  • DOI: 10.1080/2162402X.2018.1442999
  • Peer Reviewed
• [Journal Article] Minimally invasive esophagectomy may contribute to long-term respiratory function after esophagectomy for esophageal cancer. (2018)
  • Author(s): Kosumi K, Yoshida N, Okadome K, Eto T, Kuroda D, Ohuchi M, Kiyozumi Y, Nakamura K, Izumi D, Tokunaga R, Harada K, Mima K, Sawayama H, Ishimoto T, Iwatsuki M, Baba Y, Miyamoto Y, Watanabe M, Baba H.
  • Journal Title: Dis Esophagus. Volume: Feb 9. Pages: Epub
  • DOI: 10.1093/dote/dox153.
  • Peer Reviewed
• [Journal Article] The Prognostic Impact of Controlling Nutritional Status (CONUT) in Intrahepatic Cholangiocarcinoma Following Curative Hepatectomy: A Retrospective Single Institution Study. (2018)
  • Author(s): Miyata T, Yamashita YI, Higashi T, Taki K, Izumi D, Kosumi K, Tokunaga R, Nakagawa S, Okabe H, Imai K, Hashimoto D, Chikamoto A, Baba H.
  • Journal Title: World J Surg. Volume: 42(4) Pages: 1085-1091.
  • DOI: 10.1007/s00268-017-4214-1.
  • Peer Reviewed
• [Journal Article] Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells. (2017)
  • Author(s): Gu M, Nishihara R, Chen Y, Li W, Shi Y, Masugi Y, Hamada T, Kosumi K, Liu L, da Silva A, Nowak JA, Twombly T, Du C, Koh H, Li W, Meyerhardt JA, Wolpin BM, Giannakis M, Aguirre AJ, Bass AJ, Drew DA, Chan AT, Fuchs CS, Qian ZR, Ogino S.
  • Journal Title: Oncotarget. Volume: 8(50) Pages: 87379-87389
  • DOI: 10.18632/oncotarget.20972
  • Peer Reviewed
• [Journal Article] Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer. (2017)
  • Author(s): Masugi Y, Nishihara R, Hamada T, Song M, da Silva A, Kosumi K, Gu M, Shi Y, Li W, Liu L, Nevo D, Inamura K, Cao Y, Liao X, Nosho K, Chan AT, Giannakis M, Bass AJ, Hodi FS, Freeman GJ, Rodig SJ, Fuchs CS, Qian ZR, Nowak JA, Ogino S.
  • Journal Title: Cancer Immunol Res. Volume: 5(11) Pages: 1046-1055
  • DOI: 1158/2326-6066.CIR-17-0122
  • Peer Reviewed
• [Journal Article] Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index. (2017)
  • Author(s): Shi Y, Qian ZR, Zhang S, Li W, Masugi Y, Li T, Chan JA, Yang J, Da Silva A, Gu M, Liu L, Hamada T, Kosumi K, Dutton T, Brais LK, Nishihara R, Fuchs CS, Ogino S, Kulke MH.
  • Journal Title: Pancreas. Volume: 46(10) Pages: 1347-1353
  • DOI: 10.1097/MPA.0000000000000944.
  • Peer Reviewed
• [Journal Article] Monitoring sputum culture in resected esophageal cancer patients with preoperative treatment. (2017)
  • Author(s): Kosumi K, Baba Y, Yamashita K, Ishimoto T, Nakamura K, Ohuchi M, Kiyozumi Y, Izumi D, Tokunaga R, Harada K, Shigaki H, Kurashige J, Iwatsuki M, Sakamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Dis Esophagus. Volume: 30(12) Pages: 1-9
  • DOI: 10.1093/dote/dox092.
  • Peer Reviewed
• [Journal Article] Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor. (2017)
  • Author(s): Liu L, Nishihara R, Qian ZR, Tabung FK, Nevo D, Zhang X, Song M, Cao Y, Mima K, Masugi Y, Shi Y, da Silva A, Twombly T, Gu M, Li W, Hamada T, Kosumi K, Inamura K, Nowak JA, Drew DA, Lochhead P, Nosho K, Wu K, Wang M, Garrett WS, Chan AT, Fuchs CS, Giovannucci EL, Ogino S.
  • Journal Title: Gastroenterology Volume: 153(6) Pages: 1517-1530.e14.
  • DOI: 10.1053/j.gastro.2017.08.045.
  • Peer Reviewed
• [Journal Article] Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status. (2017)
  • Author(s): Hanyuda A, Cao Y, Hamada T, Nowak JA, Qian ZR, Masugi Y, da Silva A, Liu L, Kosumi K, Soong TR, Jhun I, Wu K, Zhang X, Song M, Meyerhardt JA, Chan AT, Fuchs CS, Giovannucci EL, Ogino S, Nishihara R.
  • Journal Title: Eur J Epidemiol. Volume: 32(5) Pages: 393-407
  • DOI: 10.1007/s10654-017-0254-y.
  • Peer Reviewed
• [Journal Article] Comparison of systemic inflammatory and nutritional scores in colorectal cancer patients who underwent potentially curative resection. (2017)
  • Author(s): Tokunaga R, Sakamoto Y, Nakagawa S, Izumi D, Kosumi K, Taki K, Higashi T, Miyata T, Miyamoto Y, Yoshida N, Baba H.
  • Journal Title: Int J Clin Oncol. Volume: 22(4) Pages: 740-748
  • DOI: 10.1007/s10147-017-1102-5.
  • Peer Reviewed
• [Journal Article] Preoperative controlling nutritional status (CONUT) is useful to estimate the prognosis after esophagectomy for esophageal cancer. (2017)
  • Author(s): Yoshida N, Harada K, Baba Y, Kosumi K, Iwatsuki M, Kinoshita K, Nakamura K, Sakamoto Y, Miyamoto Y, Karashima R, Mima K, Sawayama H, Ohuchi M, Chikamoto A, Imamura Y, Watanabe M, Baba H.
  • Journal Title: Langenbecks Arch Surg. Volume: 402(2) Pages: 333-341
  • DOI: 10.1007/s00423-017-1553-1.
  • Peer Reviewed
• [Presentation] Bifidobacterium Genus in Colorectal Carcinoma Tissue in relation to Tumor Characteristics and Patient Survival. (2018)
  • Author(s): Borowsky J, Kosumi K*, Hamada T, Koh H, Bullman S, Twombly TS, Masugi Y, Liu L, da Silva A, Chen Y, Du C, Gu M, Li C, Li W, Liu H, Shi Y, Song M, Nosho K, Nowak JA, Nishihara R, Baba H, Zhang X, Wu K, Huttenhower C, Garrett WS, Meyerson M, Lennerz JK, Giannakis M, Chan AT, Meyerhardt JA, Fuchs CS, Ogino S.
  • Organizer: 1.ASIP Annual Meeting at Experimental Biology 2018
• [Presentation] Bifidobacterium genus in colorectal carcinoma tissue in relation to tumor characteristics and patient survival. (2018)
  • Author(s): Kosumi K, Hamada T, Koh H, Borowsky J, Bullman S, Twombly TS, Masugi Y, Liu L, da Silva A, Chen Y, Du C, Gu M, Li C, Li W, Liu H, Shi Y, Song M, Nosho K, Nowak JA, Nishihara R, Baba H, Zhang X, Wu K, Huttenhower C, Garrett WS, Meyerson M, Lennerz JK, Giannakis M, Chan AT, Meyerhardt JA, Fuchs CS, Ogino S
  • Organizer: The 4th International Molecular Pathological Epidemiology (MPE) Meeting.