Clarification of the mechanism giving rise to metastasis by the analysis of gene expression in bone marrow and peripheral blood in cancer patients

• Project/Area Number: 19390336
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyushu University
• Principal Investigator: KOSHI Mimori Kyushu University, 生体防御医学研究所, 助教 (50322748)
• Co-Investigator(Kenkyū-buntansha): HIROSHI Inoue 九州大学, 生体防御医学研究所, 共同研究員 (90203249) ; HIDESHI Ishii 九州大学, 生体防御医学研究所, 学術研究員 (10280736)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2008: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 癌転移 / EPC / HPC / 末梢血 / 骨髄 / 癌細胞 / 宿主側因子 / EMT / 細胞周期制御 / 造腫瘍能 / ニッチ / ITC / 消化器癌 / 転移能予測因子 / 末梢血液 / VEGFR-1

Research Abstract

消化器癌の転移・再発の成立においては、癌側因子と宿主側因子とが転移形成に必須の新たな「転移巣社会」を形成すると推察されるため、両面から俯瞰的研究により転移再発機構を解明し、診断・治療の標的を求めることが重要である。われわれはその観点から、特に、1)癌細胞における転移再発促進機構および2)宿主側におけるその幇助機構の二つの側面から検討している(Ann Surg Oncol 2009 16:1070-1)。
今年度中に報告しえた成果は、癌細胞より直接分泌され浸潤・転移に重要な役割を担うu-PAR/u-PA (胃癌Br J Cancer 2008 ; 100:159-3、乳癌 Ann Surg Oncol 2009 in press)、MT1-MMP(Ann Surg Oncol 2008 ; 15 : 2934-42)の胃癌における重要な意義を明らかにした。また、MMP1については血清における蛋白測定の意義を明らかにした(Clin Cancer Res 投稿中)。さらに大腸癌において癌細胞のEMT を誘導する新規分子を同定したが同分子は、特にCD133陽性細胞において過剰発現した場合造腫瘍能を有することを明らかにした(Nat Med 投稿中)。さらに胃癌においてもEMT 誘導が生じることも明らかにしており、VEGFR1 を発現する胃癌細胞が骨髄中において過剰発現することが高い悪性度に関与することを示した(Gut, revise 中)。細胞周期関連分子としては、G0 期を誘導する分子の原発巣における役割を明らかにした(Cancer Res 2009 in press)。一方、宿主側の転移幇助機構としては、癌幹細胞のニッチとなる骨髄前駆細胞由来のVEGFR1 の意義を明らかにしたが(Clin Cancer Res 2008 ; 14 : 2609-16)、血管内皮前駆細胞由来のId1 の臨床的意義を明らかにした(Br J Cancer, minor revise 中)。

Research Products

• [Journal Article] p53-Altered FBXW7 Expression Determines Poor Prognosis in Gastric Cancer Cases (2009)
  • Author(s): Yokobori T, Mimori K, Iwatsuki M, Ishii H, Onoyama I, Fukagawa T, Kuwano H, Nakayama KI and Mori M.
  • Journal Title: Cancer Res
• [Journal Article] Over- and under-expressed microRNAs in human colorectal cancer (2009)
  • Author(s): Motoyama K, Inoue H, Takatsuno Y, Tanaka F, Mimori K, Uetake H, Sugihara K and Mori M.
  • Journal Title: Int J Oncol 34(4) Pages: 1069-75
• [Journal Article] Preoperative u-PAR Gene Expression in Bone Marrow Indicates the Potential Power of Recurrence in Breast Cancer Cases (2009)
  • Author(s): Mimori K, Kataoka A, Yamaguchi H, Masuda N, Kosaka Y, Ishii H, Ohno S and Mori M.
  • Journal Title: Ann Surg Oncol
• [Journal Article] Important matters to identify robust markers for metastasis and recurrence in solid cancer (2009)
  • Author(s): Mimori K, Iwatsuki M, Yokobori T and Mori M.
  • Journal Title: Ann Surg Oncol 16(4) Pages: 1070-1
• [Journal Article] Clinical significance of LAMB3 and COL7A1 mRNA in esophageal squamous cell carcinoma (2009)
  • Author(s): Kita Y, Mimori K, Tanaka F, Matsumoto T, Haraguchi N, Ishikawa K, Matsuzaki S, Fukuyoshi Y, Inoue H, Natsugoe S, Aikou T and Mori M
  • Journal Title: Eur J Surg Oncol 35(1) Pages: 52-8
• [Journal Article] Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases (2009)
  • Author(s): Kita Y, Fukagawa T, Mimori K, Kosaka Y, Ishikawa K, Aikou T, Natsugoe S, Sasako M and Mori M.
  • Journal Title: Br J Cancer 100(1) Pages: 153-9
• [Journal Article] A platinum agent resistance gene, POLB, is a prognostic indicator in colorectal cancer (2009)
  • Author(s): Iwatsuki M, Mimori K, Yokobori T, Tanaka F, Tahara K, Inoue H, Baba H and Mori M.
  • Journal Title: J Surg Oncol
• [Journal Article] p53-altered FBXW7 expression determines poor prognosis in gastric cancer cases (2009)
  • Author(s): Yokobori T, Mimori K, et al.
  • Journal Title: Cancer Res (in press) (in press)
  • Peer Reviewed
• [Journal Article] Mutations of epidermal growth factor receptor in colon cancer indicate susceptibility or resistance to gefitinib (2008)
  • Author(s): Zhang X, Nagahara H, Mimori K, Inoue H, Sawada T, Ohira M, Hirakawa K and Mori M.
  • Journal Title: Oncol Rep 19(6) Pages: 1541-4
• [Journal Article] Activin a causes cancer cell aggressiveness in esophageal squamous cell carcinoma cells (2008)
  • Author(s): Yoshinaga K, Yamashita K, Mimori K, Tanaka F, Inoue H and Mori M.
  • Journal Title: Ann Surg Oncol 15(1) Pages: 96-103
• [Journal Article] Activin A enhances MMP-7 activity via the transcription factor AP-1 in an esophageal squamous cell carcinoma cell line (2008)
  • Author(s): Yoshinaga K, Mimori K, Inoue H, Kamohara Y, Yamashita K, Tanaka F and Mori M.
  • Journal Title: Int J Oncol 33(3) Pages: 453-9
• [Journal Article] Efficient identification of a novel cancer/testis antigen for immunotherapy using three-step microarray analysis (2008)
  • Author(s): Yokoe T, Tanaka F, Mimori K, Inoue H, Ohmachi T, Kusunoki M and Mori M.
  • Journal Title: Cancer Res 68(4) Pages: 1074-82
• [Journal Article] Prognostic value of tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma (2008)
  • Author(s): Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, Ohta M, Kitano S and Mori M.
  • Journal Title: Eur J Surg Oncol 34(2) Pages: 173-9
• [Journal Article] Clinical significance of ApoE expression in human gastric cancer (2008)
  • Author(s): Sakashita K, Tanaka F, Zhang X, Mimori K, Kamohara Y, Inoue H, Sawada T, Hirakawa K and Mori M.
  • Journal Title: Oncol Rep 20(6) Pages: 1313-9
• [Journal Article] Clinical significance of low expression of Prostasin mRNA in human gastric cancer (2008)
  • Author(s): Sakashita K, Mimori K, Tanaka F, Tahara K, Inoue H, Sawada T, Ohira M, Hirakawa K and Mori M.
  • Journal Title: J Surg Oncol 98(7) Pages: 559-64
• [Journal Article] Clinical significance of loss of Fhl1 expression in human gastric cancer (2008)
  • Author(s): Sakashita K, Mimori K, Tanaka F, Kamohara Y, Inoue H, Sawada T, Hirakawa K and Mori M.
  • Journal Title: Ann Surg Oncol 15(8) Pages: 2293-300
• [Journal Article] Prognostic relevance of Tensin4 expression in human gastric cancer (2008)
  • Author(s): Sakashita K, Mimori K, Tanaka F, Kamohara Y, Inoue H, Sawada T, Hirakawa K and Mori M.
  • Journal Title: Ann Surg Oncol 15(9) Pages: 2606-13
• [Journal Article] Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer (2008)
  • Author(s): Ohta M, Mimori K, Fukuyoshi Y, Kita Y, Motoyama K, Yamashita K, Ishii H, Inoue H and Mori M.
  • Journal Title: Br J Cancer 98(2) Pages: 410-7
• [Journal Article] PDGF-BB is a novel prognostic factor in colorectal cancer (2008)
  • Author(s): Nakamura Y, Tanaka F, Yoshikawa Y, Mimori K, Inoue H, Yanaga K and Mori M.
  • Journal Title: Ann Surg Oncol 15(8) Pages: 2129-36
• [Journal Article] Clinical significance of BMP7 in human colorectal cancer (2008)
  • Author(s): Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, Sugihara K and Mori M.
  • Journal Title: Ann Surg Oncol 15(5) Pages: 1530-7
• [Journal Article] Identification of the expression profile of apoptotic esophageal cancer cells by adenoviral-fragile histidine triad treatment (2008)
  • Author(s): Mimori K, Ishii H, Inoue H, Barnard GF and Mori M.
  • Journal Title: J Gastroenterol Hepatol 23 Suppl 2
• [Journal Article] Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1 (2008)
  • Author(s): Mimori K, Fukagawa T, Kosaka Y, Kita Y, Ishikawa K, Etoh T, Iinuma H, Sasako M and Mori M.
  • Journal Title: Clin Cancer Res 14(9) Pages: 2609-16
• [Journal Article] A large-scale study of MT1-MMP as a marker for isolated tumor cells in peripheral blood and bone marrow in gastric cancer cases (2008)
  • Author(s): Mimori K, Fukagawa T, Kosaka Y, Ishikawa K, Iwatsuki M, Yokobori T, Hirasaki S, Takatsuno Y, Sakashita H, Ishii H, Sasako M and Mori M.
  • Journal Title: Ann Surg Oncol 15(10) Pages: 2934-42
• [Journal Article] Clinical significance of LAMB3 and COL7A1 mRNA in esophageal squamous cell carcinoma (2008)
  • Author(s): Kita Y, Mimori K, Tanaka F, Matsumoto T, Haraguchi N, Ishikawa K, Matsuzaki S, Fukuyoshi Y, Inoue H, Natsugoe S, Aikou T and Mori M
  • Journal Title: Eur J Surg Oncol
• [Journal Article] The search for cancer stem cells in hepatocellular carcinoma (2008)
  • Author(s): Kamohara Y, Haraguchi N, Mimori K, Tanaka F, Inoue H, Mori M and Kanematsu T
  • Journal Title: Surgery 144(2) Pages: 119-24
• [Journal Article] Mitotic centromere-associated kinesin is a novel marker for prognosis and lymph node metastasis in colorectal cancer (2008)
  • Author(s): Ishikawa K, Kamohara Y, Tanaka F, Haraguchi N, Mimori K, Inoue H and Mori M
  • Journal Title: Br J Cancer 98(11) Pages: 1824-9
• [Journal Article] Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes (2008)
  • Author(s): Ishii H, Mimori K, Ishikawa K, Okumura H, Pichiorri F, Druck T, Inoue H, Vecchione A, Saito T, Mori M and Huebner K
  • Journal Title: Cancer Res 68(10) Pages: 3662-70
• [Journal Article] Cancer stem cells and chemoradiation resistance (2008)
  • Author(s): Ishii H, Iwatsuki M, Ieta K, Ohta D, Haraguchi N, Mimori K and Mori M
  • Journal Title: Cancer Sci 99(10) Pages: 1871-7
• [Journal Article] Biological and genetic characteristics of tumor-initiating cells in colon cancer (2008)
  • Author(s): Ieta K, Tanaka F, Haraguchi N, Kita Y, Sakashita H, Mimori K, Matsumoto T, Inoue H, Kuwano H and Mori M
  • Journal Title: Ann Surg Oncol 15(2) Pages: 638-48
• [Journal Article] CD133+CD44+population efficiently enriches colon cancer initiating cells (2008)
  • Author(s): Haraguchi N, Ohkuma M, Sakashita H, Matsuzaki S, Tanaka F, Mimori K, Kamohara Y, Inoue H and Mori M.
  • Journal Title: Ann Surg Oncol 15(10) Pages: 2927-33
• [Journal Article] Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1 (2008)
  • Author(s): Mimori K, et al.
  • Journal Title: Clin Cancer Res 14 Pages: 2609-16
  • Peer Reviewed
• [Journal Article] Expression of uPAR mRNA in peripheral blood is a favorite marker for metastasis in gastric cancer cases. (2008)
  • Author(s): Kita Y, Fukagawa T, Mimori K, et al.
  • Journal Title: Br J Cancer 100 Pages: 153-9
  • Peer Reviewed
• [Journal Article] Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular. endothelial growth factor receptor-1 (2008)
  • Author(s): 三森 功士, ほか
  • Journal Title: Clinical Cancer Research (In press)
  • Peer Reviewed
• [Journal Article] Fhit-deficient hematopoietic stem cells survive hydroquinone treatment long-term,carrying precancerous alterations (2008)
  • Author(s): 石井 秀始、三森 功士, ほか
  • Journal Title: Cancer Research (In press)
  • Peer Reviewed
• [Journal Article] A large-scale study of MTl-MMP as a marker for isolated tumor cells in peripheral blood and bone marrow in gastric cancer cases. (2008)
  • Author(s): 三森 功士, ほか
  • Journal Title: Annals of Surgical Oncology (In press)
  • Peer Reviewed
• [Journal Article] Clinical significance of growth differentiation factor 11 in colorectal cancer (2007)
  • Author(s): Yokoe T, Ohmachi T, Inoue H, Mimori K, Tanaka F, Kusunoki M and Mori M
  • Journal Title: Int J Oncol 31(5) Pages: 1097-101
• [Journal Article] TIMP-3 and Phosphatidylinositol 3-kinase genes were found to be related to the progression of colon cancer in a comparison of pneumoperitoneum and laparotomy in a murine model (2007)
  • Author(s): Tanaka F, Sonoda H, Okamoto M, Mimori K, Utsunomiya T, Inoue H, Hanai T and Mori M
  • Journal Title: Surg Today 37 Pages: 220-5
  • NAID: 10018873190
• [Journal Article] Identification of EGFR mutations in esophageal cancer (2007)
  • Author(s): Sudo T, Mimori K, Nagahara H, Utsunomiya T, Fujita H, Tanaka Y, Shirouzu K, Inoue H and Mori M
  • Journal Title: Eur J Surg Oncol 33(1) Pages: 44-8
• [Journal Article] Opa interacting protein 5 (OIP5) is a novel cancer-testis specific gene in gastric cancer (2007)
  • Author(s): Nakamura Y, Tanaka F, Nagahara H, Ieta K, Haraguchi N, Mimori K, Sasaki A, Inoue H, Yanaga K and Mori M
  • Journal Title: Ann Surg Oncol 14(2) Pages: 885-92
• [Journal Article] Clinicopathological and biological significance of mitotic centromere-associated kinesin overexpression in human gastric cancer (2007)
  • Author(s): Nakamura Y, Tanaka F, Haraguchi N, Mimori K, Matsumoto T, Inoue H, Yanaga K and Mori M
  • Journal Title: Br J Cancer 97(4) Pages: 543-9
• [Journal Article] Loss of MAL expression in precancerous lesions of the esophagus (2007)
  • Author(s): Mimori K, Nishida K, Nakamura Y, Ieta K, Yoshikawa Y, Sasaki A, Ishii H, Alonso MA and Mori M
  • Journal Title: Ann Surg Oncol 14(5) Pages: 1670-7
• [Journal Article] Disseminated isolated tumor cells in bone marrow of esophageal cancer cases (2007)
  • Author(s): Mimori K, Kosaka Y, Hirasaki H, Kita Y, Moriyama N and Mori M
  • Journal Title: Esophagus Pages: 29-33
• [Journal Article] Clinical significance of the loss of MATS1 mRNA expression in colorectal cancer (2007)
  • Author(s): Kosaka Y, Mimori K, Tanaka F, Inoue H, Watanabe M and Mori M
  • Journal Title: Int J Oncol 31(2) Pages: 333-8
• [Journal Article] Identification of the high-risk group for metastasis of gastric cancer cases by vascular endothelial growth factor receptor-1 overexpression in peripheral blood (2007)
  • Author(s): Kosaka Y, Mimori K, Fukagawa T, Ishikawa K, Etoh T, Katai H, Sano T, Watanabe M, Sasako M and Mori M
  • Journal Title: Br J Cancer 96(11) Pages: 1723-8
• [Journal Article] Tripartite motif-containing 29 (TRIM29) is a novel marker for lymph node metastasis in gastric cancer (2007)
  • Author(s): Kosaka Y, Inoue H, Ohmachi T, Yokoe T, Matsumoto T, Mimori K, Tanaka F, Watanabe M and Mori M
  • Journal Title: Ann Surg Oncol 14(9) Pages: 2543-9
• [Journal Article] Rad9 modulates the P21WAF1 pathway by direct association with p53 (2007)
  • Author(s): Ishikawa K, Ishii H, Murakumo Y, Mimori K, Kobayashi M, Yamamoto K, Mori M, Nishino H, Furukawa Y and Ichimura K
  • Journal Title: BMC Mol Biol 8(37)
• [Journal Article] Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression (2007)
  • Author(s): Ieta K, Ojima E, Tanaka F, Nakamura Y, Haraguchi N, Mimori K, Inoue H, Kuwano H and Mori M
  • Journal Title: Int J Cancer 121(1) Pages: 33-8
• [Journal Article] BAC clones related to prognosis in patients with esophageal squamous carcinoma : an array comparative genomic hybridization study (2007)
  • Author(s): Hirasaki S, Noguchi T, Mimori K, Onuki J, Morita K, Inoue H, Sugihara K, Mori M and Hirano T
  • Journal Title: The oncologist 12(4) Pages: 406-17
• [Journal Article] Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells
  • Author(s): Saiki Y, Ishimaru S, Mimori K, Takatsuno Y, Nagahara M, Iwatsuki M, Ishii H, Yamada K and Mori M.
  • Journal Title: Ann Surg Oncol (in press)
• [Presentation] Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells (2009)
  • Author(s): Mimori K, et al.
  • Organizer: The 62^<nd> Society of Surgical Oncology
  • Place of Presentation: Phoenix Convention Ctr.
  • Year and Date: 2009-03-05
• [Presentation] Clinical significance of u-PAR gene expression in peripheral blood and bone marrow in breast cancer cases (2008)
  • Author(s): Mimori K, Yokobori Y, Iwatsuki M, Sakashita K, Tanaka F, Kamohara Y, Inoue H, Mori M
  • Organizer: The Society of Surgical Oncology, 61st Annual Cancer Symposium
  • Place of Presentation: Chicago
  • Year and Date: 2008-03-15
• [Presentation] Comprehensive analysis of the mechanism of metastasis in cancer patients (2008)
  • Author(s): MimoriK,Mori M
  • Organizer: Department of molecular biology
  • Place of Presentation: immunology and medical genetics Special Seminar of The Ohio State University Comprehensive Cancer Center, Colombus, OH.
  • Year and Date: 2008-03-14
• [Presentation] Clinical significance of u-PAR gene expression in peripheral blood and bone marrow in breast cancer cases (2008)
  • Author(s): 三森 功士, ほか
  • Organizer: 第61回米国腫瘍外科学会
  • Place of Presentation: シカゴ市
  • Year and Date: 2008-03-14
• [Presentation] 食道発癌機構における癌抑制遺伝子FHITの役割の解明 (2008)
  • Author(s): 三森功士、井上裕、森正樹
  • Organizer: 第63回日本消化器外科学会定期学術総会
  • Place of Presentation: 札幌
• [Presentation] 難治性食道癌における放射線化学療法抵抗性とFHIT消失との関係について (2008)
  • Author(s): 三森功士、石井秀始、主藤朝也、永原央、井上裕、森正樹
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Identification of the expression profile of apoptotic esophageal cancer cells by adenoviral-fragile histidine triad treatment (2008)
  • Author(s): Mimori K, Ishii H, Inoue H,, Barnard GF,Mori M
  • Organizer: The 12th Taishotoyama International Symposium on Gastroenterology
  • Place of Presentation: Shimoda
• [Presentation] Characteristics of Colon Cancer-Initiating Cells (2008)
  • Author(s): Ishii H, Ieta K, Tanaka F, Haraguchi N, Kita Y, Sakashita H, Mimori K, Matsumoto T, Inoue H, Kuwano H,, Mori M
  • Organizer: The 36th Congress of the International Society of Oncology & BioMarkers (ISOBM2008)
  • Place of Presentation: Tokyo