消化器がんの進展に関連する分子と治療・予後に関する研究

• Project/Area Number: 12218234
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Sapporo Medical University
• Principal Investigator: 今井 浩三 札幌医科大学, 学長 (60117603)
• Co-Investigator(Kenkyū-buntansha): 遠藤 高夫 札幌医科大学, 医学部, 助教授 (40191928) ; 賀佐 伸省 札幌医科大学, 医学部, 教授 (10142712) ; 有村 佳昭 札幌医科大学, 医学部, 助手 (80305218) ; 安達 正晃 札幌医科大学, 医学部, 助手 (70240926)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥171,700,000 (Direct Cost: ¥171,700,000); Fiscal Year 2004: ¥34,700,000 (Direct Cost: ¥34,700,000); Fiscal Year 2003: ¥35,000,000 (Direct Cost: ¥35,000,000); Fiscal Year 2002: ¥35,000,000 (Direct Cost: ¥35,000,000); Fiscal Year 2001: ¥33,000,000 (Direct Cost: ¥33,000,000); Fiscal Year 2000: ¥34,000,000 (Direct Cost: ¥34,000,000)
• Keywords: 消化器がん / マトリライシン / 早期大腸がん / 膵がん / ムチン分子 / 予後因子 / 食道バレット粘膜 / 消火器がん / DCC / KAI-1

Research Abstract

消化器癌について、癌浸潤、転移に関連する分子あるいは遺伝子の中から、治療選択や予後と深いつながりのある生体マーカーを見出そうとした。その結果、マトリライシンは大腸癌の浸潤、転移に関連する重要な分子であるばかりでなく、粘膜下層浸潤食道扁平上皮癌(以下、sm食道癌)のリンパ節転移に深く関わっていることを明らかにした。マトリライシンはsm食道癌の浸潤先端部に発現し、多変量解析においてリンパ節転移の有意なリスクファクターであるばかりでなく、誤差逆伝播アルゴリズムを用いたリンパ節転移予測ANNモデルにおいて、最も有意なリスクファクターであった。本モデルに関して多数の臨床例で実証実験を開始した。また、sm食道癌手術例の長期観察例において、マトリライシン陽性群は予後が有意に悪いことを認めた。これらの成績は、マトリライシンが重要な標的分子となり得ることを示しており、マトリライシン・アンチセンス投与により、食道癌細胞の浸潤能の低下を認めた。さらに、マトリライシンに対する阻害剤について検討を進めている。また、sm食道癌に先行して、多数の臨床例で実証実験を行ったsm大腸癌のANNモデルによるリンパ節転移予測システムの有用性を強く示唆する結果を得た。<BR>
さらに、食道バレット粘膜について拡大内視鏡を用いてpit pattern分類を行い、pit4および5には有意に腸型ムチン形質の発現が高く、発癌している例も経験した。プロトンポンプインヒビター等の予防的な投与により陽上皮化生の消失が認められるか等についても多数例について検討を開始した。

Research Products

• [Journal Article] Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. (2005)
  • Author(s): Murai M, Toyota M et al.
  • Journal Title: Clin Cancer Res. 11 Pages: 1021-1027
• [Journal Article] Poly(ADP-ribose) polymerase-1 (PARP-1) is a component of the oncogenic T-cell factor-4 (TCF-4)/β-catenin complex (2005)
  • Author(s): Idogawa M, Imai K et al.
  • Journal Title: Gastroenterology 128(In press)
• [Journal Article] The Ras Effector RASS2 is a novel tumor suppressor gene in human colorectal cancer. (2005)
  • Author(s): Akino K, Toyota M et al.
  • Journal Title: Gastroenterology 128(In press)
• [Journal Article] Epigenetic inactivation of SFRP's complements genetic alterations to allow constitutive Wnt pathway signaling in human colorectal cancer. (2004)
  • Author(s): Suzuki H, Toyota M, Imai K et al.
  • Journal Title: Nat.Genet. 36 Pages: 417-422
  • NAID: 130004436353
• [Journal Article] Epigenetic inactivation of class II transactivator (CIITA) is associated with absence of imterferon-γ induced HLA-DR expression in colorectal and gastric cancer cells. (2004)
  • Author(s): Satoh A, Toyota M, Imai K et al.
  • Journal Title: Oncogene 23 Pages: 8876-8886
• [Journal Article] Synergistic effect of histone deacetylase inhibitors FK228 and m-carboxycinnamic acid bis-hydroxamide with proteasome inhibitors PSI and PS-341 against gastrointestinal adenocarcinoma cells. (2004)
  • Author(s): Adachi K, Imai K et al.
  • Journal Title: Clin Cancer Res. 10 Pages: 3853-3862
• [Publications] Yamamoto H, Imai K, et al.: "Gastrointestinal cancer of the microsatellite mutator phenotype pathway."Adv. Cancer Res.. (in press). (2003)
• [Publications] Takekawa M, Imai K, et al.: "Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta."EMBO J.. 21. 6473-6482 (2002)
• [Publications] Kikuchi, T, Imai K, et al.: "Regional methylation and histone deacethylation of p57KIP2 associated with Gene silencing in human tumors."Oncogene. 21. 2741-2740 (2002)
• [Publications] Naishiro Y, Imai K, et al.: "Identification of insulin-like growth factor binding protein-2 as an immediate target of the beta-catenin and T cell factor/lymphoid enhancer factor complex."Cancer Res.. (in press). (2003)
• [Publications] Sasaki Y, Imai K, et al.: "The p53 family member genes are involved in the notch signal pathway."J.Biol.Chem.. 227. 719-724 (2002)
• [Publications] Nakamura A, Imai K, et al.: "New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression : its relationship with potential for malignancy."J.Pathol.. 197. 201-210 (2002)
• [Publications] Yamamoto H, Imai K, et al.: "Res.Adv.Cancer (Matrix metalloproteinase matrilysin in the progression of cancers of the digestive organs.) PP121-129"Global Research Network. 308 (2002)
• [Publications] Yamamoto H, Imai K, et al.: "Gastrointestinal cancer of the microsatellite mutator phenotype pathway"Adv. Cancer Res.. (in press). (2003)
• [Publications] Takekawa M, Imai K, et al.: "Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta"EMBO J.. 21. 6473-6482 (2002)
• [Publications] Kikuchi T, Imai K, et al.: "Regional methylation and histone deacethylation of p57KIP2 associated with Gene silencing in human tumors"Oncogene. 21. 2741-2749 (2002)
• [Publications] Naishiro Y, Imai K, et al.: "Identification of insulin-like growth factor binding protein-2 as an immediate target of the beta-catenin and T cell factor/lymphoid enhancer factor complex"Cancer Res.. (in press). (2003)
• [Publications] Sasaki Y, Imai K, et al.: "The p53 family member genes are involved in the notch signal pathway"J. Biol. Chem.. 277. 719-724 (2002)
• [Publications] Nakamura A, Imai K, et al.: "New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression : its relationship with potential for malignancy"J. Pathol.. 197. 201-210 (2002)
• [Publications] Yamamoto H, Imai K, et al.: "Res. Adv. Cancer (Matrix metalloproteinase matrilysin in the progression of cancers of the digestive organs) PP121-129"Global Research Network. 308 (2002)
• [Publications] Yamamoto H: "Gastrointestinal cancer of the microsatellite mutator phenotype pathway"Adv Cancer Res. (in press). (2002)
• [Publications] Nishimura S: "Adenovirus-mediated transfection of Caspase-8 augments anoikis and inhibits.Peritoneal dissemination of human gastric carcinoma cells"Cancer Res. 61. 7009-7014 (2001)
• [Publications] Kikuchi T: "Regional methylation and histone deacethylation of p57KIP2 associated with Gene silencing in human tumors"Oncogene. (in press). (2002)
• [Publications] Yamamoto H: "Expression of matrix metalloproteinases and tissue inhibitors of metallo-proteinases in human pancreatic adenocarcinomas:Clinicopathologic and prognostic significance of matrilysin expression"J Clin Oncol. 19. 1118-1127 (2001)
• [Publications] Sasaki Y: "Adenovirus-mediated transfer of the p53 family genes,p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines:potential application to gene therapy of colorectal cancer"Gene Therapy. 8. 1401-1408 (2001)
• [Publications] Adachi Y: "Expression of angiomodulin (tumor derived adhesion factor/MCA25) in invading tumor cells correlates with poor prognosis in human colorectal cancer"Int J Cancer. 95. 216-222 (2001)
• [Publications] Yamamoto H,Imai K. et al.: "Somatic mutation of the β2-microglubulin gene associated with unfavorable prognosis in gastrointestinal cancer of the microsatellite mutator nhenotype."Gastroenterology. 120(in press). (2001)
• [Publications] Yamamoto H,Imai K, et al.: "Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability."Cancer Res. 61(in press). (2001)
• [Publications] Takekawa M,Imai K, et al.: "p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV rediateion."EMBO J. 19. 6517-6526 (2000)
• [Publications] Suzuki H,Imai K, et al.: "Inactivation of the 14-3-3 sigma gene is associated with 5′ CpG island hypermethylation in human cancers."Cancer Res. 60. 4353-4357 (2000)
• [Publications] Shirakawa K,Imai K, et al.: "Gene targeting Flt-1 and Tie 2 inhibits tumor growth and metastases on WIBC-9, a human inflammatory cancer xenograft."Cancer Res. (in press). (2001)
• [Publications] Naishiro Y,Imai K, et al.: "Restroration of epithelial cell polarity in a colorectal cancer cell line by suppression of β-catenin/T cellfactor 4-mediated gene transactivation."Cancer Res. 61(in press). (2001)