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宿主を重視した転移の分子生物学

Research Project

Project/Area Number 09254101
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

入村 達郎  東京大学, 大学院・薬学系研究科, 教授 (80092146)

Co-Investigator(Kenkyū-buntansha) 矢守 隆夫  癌研究所, 分子薬理部, 部長(研究職) (60200854)
松浦 成昭  大阪大学, 医学部, 教授 (70190402)
宮崎 香  横浜市立大学, 木原生物学研究所, 教授 (70112068)
浜田 淳一  北海道大学, 附属癌研究施設, 講師 (50192703)
谷口 俊一郎  信州大学, 医学部・附属加齢適応研究センター, 教授 (60117166)
横田 淳  国立がんセンター研究所, 生物学部, 部長 (10191503)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥103,000,000 (Direct Cost: ¥103,000,000)
Fiscal Year 1999: ¥33,000,000 (Direct Cost: ¥33,000,000)
Fiscal Year 1998: ¥33,000,000 (Direct Cost: ¥33,000,000)
Fiscal Year 1997: ¥37,000,000 (Direct Cost: ¥37,000,000)
Keywords癌転移 / 癌の進行 / 癌と宿主の相互作用 / マトリクス / 線維芽細胞 / 脈管系 / マクロファージ / 転移のモデル / 浸潤 / 血管新生 / 癌の悪性化 / 腫瘍免疫 / 癌細胞の運動性 / 増殖因子 / 線維形成 / 自然免疫 / 微小環境 / 臓器特異性 / 細胞認識 / 液性因子
Research Abstract

癌の治療法を改善するには、癌がいかに発生するかよりも、癌がいかに宿主に障害を与えるかを解明することが重要であり、転移機構の理解はその最も重要な目標となる。「Seed and soil説」に述べられているように、癌転移の成立は癌細胞の性質と宿主の臓器の環境の両方によって規定される。特に、腫瘍を構成する不均一な癌細胞集団の一部に高転移性の癌細胞が生じる過程、転移臓器で微小転移が臨床的に問題となる転移巣として確立する過程等には宿主の影響が大きいと考えられる。宿主細胞として、結合組織系、血管系、免疫系等の細胞が重要である。本研究は、宿主の細胞に注目して高転移性癌細胞との相互作用を担う分子を同定し、新しい癌転移治療法開発の基盤を築くことを目的とした。具体的には、癌転移成立に到る過程で決定的な宿主側の分子形質を見い出すため、新しい癌転移動物実験モデル(大腸癌肝転移、肺癌縦隔リンパ節転移)を作製しその転移成立過程を詳細に検討した。更に、癌が進行する過程で転移性の高い癌細胞が生じる機構を解析した。例えば、肺癌細胞にHOXD3を強制発現すると、既知の転移関連遺伝子が発現すること、類似の発現誘導が宿主からの因子によっても起こることを示した。一方、マウス大腸癌モデルで数多くの未知の遺伝子が、高転移細胞に発現又は消失していることを、ディファレンシャルディスプレイ法により示した。転移の臓器特異性が如何に決定されるのかを、宿主因子に注目して解析し、関与している分子をepithelin precursor遺伝子産物と同定した。ラミニンγ2鎖、各種β1インテグリンなど、宿主細胞やマトリックスと癌細胞との接着・浸潤に関与する分子を同定し、臨床像との相関を明らかにした。接着から浸潤に到る過程を宿主側から制御するcalponinなどの細胞骨格系蛋白質の関与を明かにした。又、宿主の血管内皮が癌細胞由来の因子により開裂することを発見しこの因子を部分精製した。

Report

(3 results)
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (68 results)

All Other

All Publications (68 results)

  • [Publications] Fujita, K.: "Expression of MUC1 mucins in versely correlated"Brit. J. Cancer. 80. 301-308 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Iida, S.: "Interaction of human macrophage C-type lectin〜"J. Biol. Chem.. 274. 10697-10705 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Iida, S.: "N-acetylgalactosamine into consecutive〜"FEBS Lett.. 449. 230-234 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shoda, J.: "Secretory low-molecular-weight phospholi〜"Hepatology. 29. 1026-1036 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sato, K.: "Laminin 5 promotes activation and apoptosis〜"Exp. Cell Res.. 247. 451-460 (1999)

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      1999 Annual Research Report
  • [Publications] Hirabayashi, K.: "Inhibitation of cancer cell growth by polyinosinic〜"Cancer Res.. 59. 4325-4333 (1999)

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      1999 Annual Research Report
  • [Publications] Fujisaki, T.: "CD44 stimulation induces integrin-mediated〜"Cancer Res.. 59. 4427-4434 (1999)

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      1999 Annual Research Report
  • [Publications] Tsuiji, M.: "Genomic structure and chromosomal location〜"Immunogenetics. 50. 67-70 (1999)

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      1999 Annual Research Report
  • [Publications] Masaki, Y.: "Sialylated MUC1 mucin expression in normal〜"Hepato-gastroenterology. 46. 2240-2245 (1999)

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      1999 Annual Research Report
  • [Publications] Tsuji, T.: "Characterization of Mouse integrin a3 subunit〜"J. Biochem.. 125. 1183-1188 (1999)

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      1999 Annual Research Report
  • [Publications] Tamada, Y.: "Carbohydrate epitopes and mucins expressed〜"Oncol. Res.. 11. 233-241 (1999)

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      1999 Annual Research Report
  • [Publications] Higashi, M.: "Expression of MUC1 and MUC2 mucin antigens〜"Hepatology. 30. 1347-1355 (1999)

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      1999 Annual Research Report
  • [Publications] Takeda, H.: "E-cadherin function as a cis-dimer at〜"Nature Structure Biology. 6. 310-312 (1999)

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      1999 Annual Research Report
  • [Publications] Shimoyama, Y.: "Biochemical characterization and fictional〜"J. Biol. Chem.. 274. 11987-11994 (1999)

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      1999 Annual Research Report
  • [Publications] Katagiri, Y. U.: "CD44 variants but not CD44s cooperate〜"Cancer Res.. 59. 219-226 (1999)

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      1999 Annual Research Report
  • [Publications] Doki, Y.: "Mediastinal lymph node metastasis〜"Br. J. Cancer. 79. 1121-1126 (1999)

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      1999 Annual Research Report
  • [Publications] Yamori, T.: "Potent antitumor activity of MS-247〜"Cancer Res.. 59. 4042-4049 (1999)

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      1999 Annual Research Report
  • [Publications] Matsumoto, J.: "Asc. a novel 22-kDa protein containing〜"J. Biol. Chem.. 274. 33835-33838 (1999)

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      1999 Annual Research Report
  • [Publications] Mizuochi,S.: "Immunohistochemical study on a macrophage calcium-type lectin 〜." Glycoconjugate J.15. 397-404 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakatsubo,N.: "Direct evidence of nitric oxide production from 〜." FEBS Lett.427. 263-266 (1998)

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      1998 Annual Research Report
  • [Publications] Mizuno,N.: "Importance of heputic first-pass removal in 〜." J.Hepatol. 28. 865-877 (1998)

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      1998 Annual Research Report
  • [Publications] Koike,C.: "How platelet aggregation affects B16BL6 〜." FEBS Lett.427. 286-290 (1998)

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      1998 Annual Research Report
  • [Publications] Kano,M.: "Effects of longterm orsodeoxycholate administration." Hepatology. 28. 302-313 (1998)

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      1998 Annual Research Report
  • [Publications] Mizuno.N: "Mechanizm of initial distribution of blood-borne 〜." Hepatology. 28. 878-885 (1998)

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      1998 Annual Research Report
  • [Publications] Tsuiji,H.: "Novel carbohydrate specificity of a monoclonal〜." Biochem.Biophys.Res.Commun. 253. 374-381 (1998)

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      1998 Annual Research Report
  • [Publications] Nemoto,Y.: "Comparison of 16 human colon carcinoma cell 〜." Clin.Exp.Metastasis. 16. 569-576 (1998)

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      1998 Annual Research Report
  • [Publications] Endo,T.: "Expression of solfated carbohydrate chain 〜." J.Gastoroenterol. 33. 811-815 (1998)

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      1998 Annual Research Report
  • [Publications] Loveless,R: "Monoclonal antibody 91.9 Hraized against 〜." Glycobiol.8. 1237-1242 (1998)

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      1998 Annual Research Report
  • [Publications] Fujita,K.: "Expression on MUC1 mucins inversely correlated" Brit.J.Cancer. <in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Tsuiji,H.: "Malignant and other properties of of human 〜." Clin.Exp.Metastasis. <in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Yonezawa,S.: "MUC-1 mucin expression in invasive areas 〜." Pathology Int.48. 319-322 (1998)

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      1998 Annual Research Report
  • [Publications] Hosoi,T.: "Coordinated binding of sugar,calcium and 〜." Glycobiology. 8. 791-798 (1998)

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      1998 Annual Research Report
  • [Publications] Shirotani,K.: "Purification of nuclear proteins that 〜." J.Biochem.124. 585-598 (1998)

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      1998 Annual Research Report
  • [Publications] Sato,K.: "Contribution of dermal macroghage trafficking 〜." J.Immonol. 161. 6835-6844 (1998)

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      1998 Annual Research Report
  • [Publications] Tsuiji,H.: "Expression of mucin-associated sulfo-Le^a 〜." Jpn.J.Cancer Res.89. 1267-1275 (1998)

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      1998 Annual Research Report
  • [Publications] Utsunomiya,T.: "Expression of MUC1 and MUC2 mucins in 〜:" Clin.Cancer Res.4. 2605-2614 (1998)

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      1998 Annual Research Report
  • [Publications] Miyata,S.: "Stimulation and celluar growth and adhesion〜." Clin.Exp.Metastasis. <in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Koshikawa,N.: "Expression of trypsin by epithelial cells 〜." J.Pathol.<in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Akatsu,T.: "Chinese hamster ovary cells expressing 〜." J.Bone Miner Res. 13. 1251-1259 (1998)

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      1998 Annual Research Report
  • [Publications] Kawada,M.: "Up-regulation of p27kipl correlates inversely 〜." Jpn.Cancer Res.89. 110-115 (1998)

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      1998 Annual Research Report
  • [Publications] Yoshikawa,H.: "Mice lacking smooth moscle calponin display 〜." Genes to Cells. <in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Go,H.: "Aogmentation in the expression of a ribosomal 〜." Biochem Molecolar Biol.Int.<in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Habelhan,H.: "PSK induces Mn-SOD in tumor tissues 〜." Cancer Immurel.Immunother.<in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Iwai,K.: "Selective transedothelial migration of 〜." Blood.<in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Iwaya,K.: "Activation of b-catenin by intrertitional 〜." Cancer Res.58. 1021-1026 (1998)

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      1998 Annual Research Report
  • [Publications] Okamoto,H.: "Docun-regulation of focal adhesion kinase〜." Clin Exp.Merastasis. 16. 234-252 (1998)

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      1998 Annual Research Report
  • [Publications] Murata,J.: "Induction of autocrine factor inhibiting 〜." Int.J.Cancer. <in press>. (1999)

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      1998 Annual Research Report
  • [Publications] Ogasawara: "Inhbitory effect of vasoactive intestinal 〜." Oncol.Res.<in press>. (1999)

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      1998 Annual Research Report
  • [Publications] 入村達郎: "腫瘍マーカー研究会誌" 腫瘍マーカー, (1998)

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      1998 Annual Research Report
  • [Publications] 森本恵.入村達郎: "実験医学・増刊" 羊土社, (1998)

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      1998 Annual Research Report
  • [Publications] Mizuochi,S.: "Uniqwe tissue distribution of a mouse macrophage C-type lectin." Glycobiology. 7. 137-146 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakamori,S.: "Expression of carbohydrate ahtigen Sialyl Leaia new funtional Prognastic factor in gastic cancer." J.Clin.Oncol.15. 816-825 (1997)

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      1997 Annual Research Report
  • [Publications] Yamamoto,K.: "Sialic acid-binding motif of Maackia amurensis lectins." J.Biochem. 121. 756-761 (1997)

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      1997 Annual Research Report
  • [Publications] Nakamori,S.: "Inrolrement of carbohydrate antigen sialyl Lewis-x in colorectal cancer metastasis." Dis.Colon.Rectum.40. 420-431 (1997)

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      1997 Annual Research Report
  • [Publications] Satoh,A.: "Modulation of cell surface lectin receptors on K562 human erythroleukemia cells induced by transfection with annexin IV cDNA" Febs.Let.405. 107-110 (1997)

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      1997 Annual Research Report
  • [Publications] Koike,C.: "Tumor cells with organ-specific metastatic ability shows distinctive trafficking in riro:analyses by positron" Can.Res.57. 3612-3619 (1997)

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      1997 Annual Research Report
  • [Publications] Nakamori,S.: "Increased endothelial cell retraction and tomor cell-inrasion by soluble factors derired from pancreatic cancer cells" Ann.Surg.Oncol.4. 361-368 (1997)

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      1997 Annual Research Report
  • [Publications] Okamoto,H.: "Down-regulation of focal adnesion kinase pp125FAK in endothelial cells retraction durirg Tumor cell inrasion" Clin.Exp.Metastasis. in press (1998)

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      1997 Annual Research Report
  • [Publications] Tumura,S.: "Association of ccmulative allelic losses with tumor aggressireness in hepatocellular Carcinoma." J.Hepatol. 27. 669-676 (1997)

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      1997 Annual Research Report
  • [Publications] Aihara,T.: "Derection of pancreatic and gastric cancer cells in peripheral ard postal blood by amplitication of Keratin 19 mRNA" Int.I.Cancer. 72. 408-411 (1997)

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      1997 Annual Research Report
  • [Publications] Hashimoto,Y: "Expression of the Elml gene,a novel gene of CCN family Soppresses in rivo-tomor growth and metastasta sps of K1735" J.Exp.Med.in press (1998)

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      1997 Annual Research Report
  • [Publications] Tari,M.: "Isolation of novel Sry-related gene that is expressed in high-melastatic k-1735 murine melanoma cells." Genomics. 39. 30-37 (1997)

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      1997 Annual Research Report
  • [Publications] Yamashita,T.: "Reciprocal control of colon-specific sulfomucin and sialosyl Tn antigen expression in human colorectal neoplasia" Virchows.Arch,. 431. 25-30 (1997)

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      1997 Annual Research Report
  • [Publications] Kimura,H.: "Distinct substrate specificities of five human α-1,3-fucosyltransferases for in viro synthesis of the sialyl Lenres" Biol.Biophy,Res.Com.237. 131-137 (1997)

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      1997 Annual Research Report
  • [Publications] Fukuda,S.: "Isolation of a norel gone showing reduced expression in metastatic colorectal carinoma cell and corcinoma" Jpn.J.Cancer Res.88. 725-731 (1997)

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      1997 Annual Research Report
  • [Publications] Lim.J: "Isolation of murine and human homolog use of the fission-yeast dis3t gene encoding a mitotic-control protein" Cancer.Res.57. 921-925 (1997)

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      1997 Annual Research Report
  • [Publications] Yamori,T.: "Anti-tumor efficacy of poclitaxel against human lung cancer xenografts" Jpn.J.Cancer Res.88. 1205-1210 (1997)

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      1997 Annual Research Report
  • [Publications] Fujii,H.: "Vaccination with B7-1+Tumor and anti-adhesion therapy with RGD pseudo-pepride(Fc-336)efficiently induce anti-metastatic effect." Clinical.Exp.Metastasis. 16(in press). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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