癌の発生とその治療困難性における癌幹細胞の遺伝学的解明

2010 Fiscal Year Annual Research Report

• Project/Area Number: 20390360
• Research Institution: Kyushu University
• Principal Investigator: 井上 裕 九州大学, 生体防御医学研究所, 共同研究員 (90203249)
• Co-Investigator(Kenkyū-buntansha): 三森 功士 九州大学, 生体防御医学研究所, 准教授 (50322748) ; 田中 文明 九州大学, 大学病院, 助教 (30332836) ; 石井 秀始 九州大学, 生体防御医学研究所, 学術研究員 (10280736)
• Keywords: 癌幹細胞 / CD13 / 活性酸素 / CD133 / CD44 / 転移再発 / 治療抵抗性

Research Abstract

癌の多様性は根治性を妨げるものであり、「原発巣におけるheterogeneity」、「転移・再発」そして「治療抵抗性」が多様性を形成している。これらの原因として癌幹細胞の存在が知られ、癌幹細胞を正確に捉え制圧することが、癌の根治を実現する上で極めて重要である。
われわれは平成21年度から22年度まで3年間助成をいただき、癌幹細胞を検出し制圧するための様々なアプローチを行い成果を上げた。初年度はLaser microdissection(LMD)を用いて発現profileを明らかにし、H21年度は癌転移において重要な役割を担う上皮間葉移行(EMT)を制御する遺伝子を同定した。本年度は特に大腸癌と肝臓癌における癌幹細胞マーカーの同定において成果を上げた。
まず、大腸癌幹細胞は造血幹細胞、神経幹細胞のマーカーとして知られるCD133が発現することが知られている。われわれは大腸癌細胞株においてCD133+細胞がCD133-細胞に比較して高い腫瘍形成能を有することを明らかにした。さらに、CD133のみならずCD44+細胞において造腫瘍能を示すことを明らかにした。
一方、肝臓癌の幹細胞マーカーとしてわれわれは、CD13発現細胞がGO期にあり、造腫瘍能を有することを明らかにした。また、CD13陽性細胞では化学/放射線による活性酸素(reactive oxygen species : ROS)誘導によるゲノムDNA損傷に対して、アポトーシスから回避させること示した。また、CD13抑制により肝癌細胞は自己複製能および造腫瘍能を喪失することを明らかにした(J. Clin Invest 2010)。
癌幹細胞を標的として治療戦略は難治性の進行癌克服のための非常に有望と考えられている。しかし正常幹細胞と癌幹細胞は多くの共通点があり単純な幹細胞シグナルの阻害のみでは癌幹細胞を特異的に標的とする治療とならず副作用の問題が生じる。今後は癌幹細胞特異的な分子の同定、またそれを治療標的するためのさらなる研究が必要とされる。

Research Products

• [Journal Article] Clinical Significance of Circulating Tumor Cells, Including Cancer Stem-Like Cells, in Peripheral Blood for Recurrence and Prognosis in Patients With Dukes' Stage B and C Colorectal Cancer (2011)
  • Author(s): Iinuma, H., Watanabe, T., Mimori, K., et al.
  • Journal Title: J Clin Oncol Volume: (CDR)
  • Peer Reviewed
• [Journal Article] Identification of HLA-A^*0201/-A^*2402-restricted CTL epitope-peptides derived from a novel cancer/testis antigen, MCAK, and induction of a specific antitumor immune response (2011)
  • Author(s): Kawamoto, M., Tanaka, F., Mimori, K., et al.
  • Journal Title: Oncol Rep Volume: 25 Pages: 469-76
  • Peer Reviewed
• [Journal Article] STC2 : a predictive marker for lymph node metastasis in esophageal squamous-cell carcinoma (2011)
  • Author(s): Kita, Y., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 261-72
  • Peer Reviewed
• [Journal Article] The correlation between clinical laboratory data and telomeric status of male patients with metabolic disorders and no clinical history of vascular events (2011)
  • Author(s): Maeda, T., Oyama, J., Higuchi, Y., Koyanagi, M., Sasaki, M., Arima, T., Mimori, K., et al.
  • Journal Title: Aging Male Volume: 14 Pages: 21-6
  • Peer Reviewed
• [Journal Article] The physical ability of Japanese female elderly with cerebrovascular disease correlates with the telomere length and subtelomeric methylation status in their peripheral blood leukocytes (2011)
  • Author(s): Maeda, T., Oyama, J., Higuchi, Y., Nishiyama, Y., Kudo, Y., Yamori, T., Nakazono, T., Arima, T., Mimori, K., et al.
  • Journal Title: Gerontology Volume: 57 Pages: 137-43
  • Peer Reviewed
• [Journal Article] Kinesin 18A expression clinical relevance to colorectal cancer progression (2011)
  • Author(s): Nagahara, M., Nishida, N., Iwatsuki, M., Ishimaru, S., Mimori, K., et al.
  • Journal Title: Int J Cancer Volume: (in press)
  • Peer Reviewed
• [Journal Article] MicroRNA-125a-5p is an independent prognostic factor in gastric cancer, and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab (2011)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Clin Cancer Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma (2011)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 535-42
  • Peer Reviewed
• [Journal Article] Identification of recurrence-related microRNAs in the bone marrow of breast cancer patients (2011)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 38 Pages: 955-62
  • Peer Reviewed
• [Journal Article] Significance of Lgr5(+ve) Cancer Stem Cells in the Colon and Rectum (2011)
  • Author(s): Takahashi, H., Ishii, H., Nishida, N., Takemasa, I., Mizushima, T., Ikeda, M., Yokobori, T., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 1166-74
  • Peer Reviewed
• [Journal Article] Hypoxia-inducible Adrenomedullin in Colorectal Cancer (2011)
  • Author(s): Uemura, M., Yamamoto, H., Takemasa, I., Mimori, K., et al.
  • Journal Title: Anticancer Res Volume: 31 Pages: 507-14
  • Peer Reviewed
• [Journal Article] Identification of Recurrence-Related microRNAs in the Bone Marrow of Breast Cancer Patients. (2010)
  • Author(s): Mimori K, Ota D, Yokobori T, Iwatsuki M, Kataoka A, Masuda N, Ishii H, Ohno S, M Mori.
  • Journal Title: Int J Oncol
  • DOI: 10.3892/ijo.2011.926
• [Journal Article] CD13 is a therapeutic target in human liver cancer stem cells. (2010)
  • Author(s): Haraguchi, N., Ishii, H., Mimori, K., et al.
  • Journal Title: J Clin Invest Volume: (CDR)
  • Peer Reviewed
• [Journal Article] Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors (2010)
  • Author(s): Hirose, H., Ishii, H., Mimor, K., et al.
  • Journal Title: Oncol Rep Volume: 23 Pages: 35-43
  • Peer Reviewed
• [Journal Article] Clinical Significance of Human Kallikrein7 Gene Expression in Colorectal Cancer. (2010)
  • Author(s): Inoue, Y., Yokobori, T., Yokoe, T., Toiyama, Y., Miki, C., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: (CDR)
  • Peer Reviewed
• [Journal Article] The Clinical Significance of Vimentin-Expressing Gastric Cancer Cells in Bone Marrow (2010)
  • Author(s): Iwatsuki, M., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: (CDR)
  • Peer Reviewed
• [Journal Article] Overexpression of SUGT1 in human colorectal cancer and its clinicopathological significance (2010)
  • Author(s): Iwatsuki, M., Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 36 Pages: 569-75
  • Peer Reviewed
• [Journal Article] Epithelial-mesenchymal transition in cancer development and its clinical significance (2010)
  • Author(s): Iwatsuki, M., Mimori, K., et al.
  • Journal Title: Cancer Sci Volume: 101 Pages: 293-9
  • Peer Reviewed
• [Journal Article] STC2 : A Predictive Marker for Lymph Node Metastasis in Esophageal Squamous-Cell Carcinoma (2010)
  • Author(s): Kita, Y., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Pages: 4
  • Peer Reviewed
• [Journal Article] Expression of C4.4A at the invasive front is a novel prognostic marker for disease recurrence of colorectal cancer (2010)
  • Author(s): Konishi, K., Yamamoto, H., Mimori, K., et al.
  • Journal Title: Cancer Sci Volume: 101 Pages: 2269-77
  • Peer Reviewed
• [Journal Article] FHIT Suppresses Inflammatory Carcinogenic Activity by Inducing Apoptosis in Esophageal Epithelial Cells (2010)
  • Author(s): Mimori, K., et al.
  • Journal Title: J Nucleic Acid Invest Volume: 101 Pages: 2269-77
  • Peer Reviewed
• [Journal Article] Serum Matrix-Metalloproteinase-1 is a Bona Fide Prognostic Marker for Colorectal Cancer (2010)
  • Author(s): Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: (CDR)
  • Peer Reviewed
• [Journal Article] Abnormal Expression of PFDN4 in Colorectal Cancer : A Novel Marker for Prognosis (2010)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: (CDR)
  • Peer Reviewed
• [Journal Article] TDGF1 is a novel predictive marker for metachronous metastasis of colorectal cancer (2010)
  • Author(s): Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 36 Pages: 563-8
  • Peer Reviewed
• [Journal Article] SCRN1 is a novel marker for prognosis in colorectal cancer (2010)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K, et al.
  • Journal Title: J Surg Oncol Volume: 101 Pages: 156-9
  • Peer Reviewed
• [Journal Article] TGM2 is a novel marker for prognosis and therapeutic target in colorectal cancer (2010)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 967-72
  • Peer Reviewed
• [Journal Article] ATP11A is a novel predictive marker for metachronous metastasis of colorctal cancer (2010)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K., et al.
  • Journal Title: Oncol Rep Volume: 23 Pages: 505-10
  • Peer Reviewed
• [Journal Article] Defined factors induce reprogramming of gastrointestinal cancer cells (2010)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K., et al.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 107 Pages: 40-5
  • Peer Reviewed
• [Journal Article] Clinicopathological and prognostic significance of PDCD4 and microRNA-21 in human gastric cancer (2010)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 36 Pages: 1089-95
  • Peer Reviewed
• [Journal Article] Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients (2010)
  • Author(s): Nagahara, M., Mimori, K, et al.
  • Journal Title: Clin Cancer Res Volume: 16 Pages: 4625-35
  • Peer Reviewed
• [Journal Article] FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma (2010)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: (CDR)
  • Peer Reviewed
• [Journal Article] FANCD2 mRNA overexpression is a bona fide indicator of lymph node metastasis in human colorectal cancer (2010)
  • Author(s): Ozawa, H., Iwatsuki, M., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 2341-8
  • Peer Reviewed
• [Journal Article] Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles (2010)
  • Author(s): Tanaka, F., Yamamoto, K., Suzuki, S., Inoue, H., Tsurumaru, M., Kajiyama, Y., Kato, H., Igaki, H., Furuta, K., Fujita, H., Tanaka, T., Tanaka, Y., Kawashima, Y., Natsugoe, S., Setoyama, T., Tokudome, S., Mimori, K., et al.
  • Journal Title: Gut Volume: (CDR)
  • Peer Reviewed
• [Journal Article] Clinical significance of ASB9 in human colorectal cancer (2010)
  • Author(s): Tokuoka, M., Miyoshi, N, Hitora, T., Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 37 Pages: 1105-11
  • Peer Reviewed
• [Journal Article] Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer : in vivo identification from hypoxic tumor cells (2010)
  • Author(s): Uemura, M., Yamamoto, H., Takemasa, I., Mimori, K., et al.
  • Journal Title: Clin Cancer Res Volume: 16 Pages: 4636-46
  • Peer Reviewed
• [Journal Article] Clinical Significance of Stanniocalcin 2 as a Prognostic Marker in Gastric Cancer (2010)
  • Author(s): Yokobori, T., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: (CDR)
  • Peer Reviewed
• [Presentation] 大腸癌細胞のゲノムCGHクラスター解析および発現アレイpathway解析による5-FU適応症例の決定 (2010)
  • Author(s): 三森功士, 他8名
  • Organizer: 第110回日本外科学会定期学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-04-09
• [Presentation] Identification of target gene enhanced by Wnt/TCF binding to the predisposition SNP rs6983267 at chromosome 8q24 in colorectal cancer cases (2010)
  • Author(s): Mimori K., et al
  • Organizer: Society of Surgical Oncology, 2010
  • Place of Presentation: St.Loius
  • Year and Date: 2010-03-05