2001 年度実績報告書

膵臓がん肝転移モデルの設立と治療薬開発への応用

研究課題

研究課題/領域番号	11557180
研究機関	東京大学
研究代表者	入村達郎東京大学, 大学院・薬学系研究科, 教授 (80092146)
研究分担者	別府倫兄順天堂大学, 医学部, 助教授 (00111542) 築地信東京大学, 大学院・薬学系研究科, 助手 (90302611) 東伸昭東京大学, 大学院・薬学系研究科, 講師 (40302616)
キーワード	膵臓がん / 肝転移 / 微少転移 / ヌードマウス / DNAアレイ / PCR / がんの進行 / 遺伝子発現
研究概要	がんの主要な部分を占める固形腫瘍の治療において、最も重要かつ深刻な問題は、転移をいかに制御するかである。膵臓がんにおいても、肝転移の発生を押さえることができかどうかで予後やQOLが大きく変わってくる。これまでに申請者らが得て来た知見から、がん転移のメカニズムはがんの種類ごとに特徴があり、これを理解した上で転移の治療を行うことがぜひとも必要であることが確実となった。本研究ではこれまでに、(1)遺伝子レベルで膵臓がん由来の微少転移の存在を予知する技術、(2)膵臓がんの肝転移の遺伝子治療のターゲットと成る遺伝子の発見、(3)膵臓がんの肝転移を治療する薬物を開発するための簡便なスクリーンシステムの設立、(4)膵臓がんの微少肝転移が臨床的に問題と成る転移巣に成長することを抑制する技術、の開発を目指して来た。先ずヌードマウスを用いたヒト膵臓癌細胞(ASPC-1細胞、Capan-1細胞、Colo357細胞)の転移モデルを確立した。当初は脾注肝転移モデルを設立し、膵臓注肝転移モデルに成功した。これらを用いて高転移性バリアントの作成を試みたが、成功しなかった。転移モデルに関しては、製薬会社に技術供与を行い(無報酬)、肝転移抑制技術の開発に寄与せしめた。(1)と(2)の目標達成は、高転移性細胞の設立に依存しているため、時間的な制約を考慮して、同時に私どもとは独立に肝臓に高転移性を持つ膵臓癌細胞の確立を試みてある程度の成功をおさめたデキサス大学MDアンダーソン癌センターのI. J. FIdler教授と共同研究を開始した。Fidler教授から寄与を受けた肝臓に高転移性を持つ膵臓癌細胞に発現する遺伝子で、低転移性の親株には発現してない遺伝子、またはその逆のケースを、DANアレイによって解析した。その結果複数の遺伝子を同定し、それらはほとんどこれまでに転移性との関連が記載されていない遺伝子であった。

研究成果

(22件)

すべてその他

すべて文献書誌 (22件)

[文献書誌] Kato K. et al.: "Distinct Orders of GalNAc Incorporation into a Peptide with Consecutive Threonines"Biochem Biophys Res Commun.. 287. 110-115 (2001)
[文献書誌] Kato K. et al.: "N-acetylgalactosamine incorporation into a peptide containing consecutive threonine residues by UDP-N-acetyl-D-galactosamlnide : polypeptide N-acetylgalactosaminyltransferases"Glycobiology. 11. 812-829 (2001)
[文献書誌] Togayachi A. et al.: "Molecular cloning and characterization of UDP-GlcNAc : Lactosylceramide B1, 3-N-Acetylgalucosaminyltransferase (B3Gn-T5), an essential enzyme for the expression of HNK-1 and Lewix X epitopes on glycolipids"J Biol Chem.. 276. 22032-22040 (2001)
[文献書誌] Yim M. et al.: "Mutated plant lectin library useful to identify different cells"Proc Nat Acad Sci USA. 98. 2222-2225 (2001)
[文献書誌] Shirota K. et al.: "Anti-metastatic effect of the sialyl lewis-x analog GSC-150 on the human colon carcinoma derived cell line KM12-HX in the mouse"Biol Pharm Bull.. 24. 316-319 (2001)
[文献書誌] Kawamoto T, et al.: "Expression of MUC1 mucins with sialylated carbohydrates at the deepest invasding sites correlates with post-surgical prognosis of pT2 carcinoma of the galbladder"Clin Cancer Res. 7. 1333-1342 (2001)
[文献書誌] Amano J. et al.: "Intestinal epithelial cells express and secrete the CD43 glycoform that contains core 2 σ-glycans"Microbes and Infect. 3. 723-728 (2001)
[文献書誌] Uwatoku R. et al.: "Kupffer cell-mediated recruitment of rat dendritic cells to the liver : roles of N-acetylgaractosamine-specific sger recerptors"Gasteroenterology. 121. 1460-1472 (2001)
[文献書誌] Morimoto M. et al.: "Fibroblast migratory factor derived from mouse colon carcinoma cells : potential roles of fibronectin in tumor stroma formation"J Cell Biochem.. 80. 635-646 (2001)
[文献書誌] Denda-Nagai K. et al.: "MUC1 in carcinoma-host interactions"Giycoconjugate J. 17. 649-658 (2000)
[文献書誌] Denda-Nagai K. et al.: "Absence of correlation of MUC1 expression to malignant behavior of renal cell carcinoma in experimental systems"Clin Exp Metastasis. 18. 71-81 (2000)
[文献書誌] Kusaka Y. et al.: "Vital immunostaining of human gastric and colorectal cancer grafted into nude mice ; a preclinical assessment of a potential adjunct to videoendoscopy"J Gastroenterol. 35. 748-752 (2000)
[文献書誌] Chun K-H. et al.: "Involvement of cytokines in the skin-to-lymph node trafficking of cells of the monocyte-macrophage lineage expressing a C-type lectin"Int Immunol.. 12. 1695-1703 (2000)
[文献書誌] Ichii S, et al.: "Initial steps in lymph node metastasis formation in an experimental system : possible involvement of recognition by macrophage C-type lectins"Cancer Immunol Immunother. 49. 1-9 (2000)
[文献書誌] Chun K-H. et al.: "Migration of dermal cells expressing a macrophage C-type lectin during the sensitization phase of delayed-type hypersensitivity"J Leukocyte Biol.. 68. 471-478 (2000)
[文献書誌] Ota M, et al.: "Involvement of cell surface glycans in adhesion of human colon carcinoma cells to liver tissue in a frozen section assay : role of endo-b-galactosidase-sensitive structures"Cancer Res.. 60. 5261-5268 (2000)
[文献書誌] Koike J, et al.: "Density-dependent induction of TNF-a release from human monocytes by immobilized P-selectin"FEBS Lett. 477. 84-88 (2000)
[文献書誌] Iida S, et al.: "Order and maximum incorporation of N-acetyl-D-galactosamine into threonine residues of MUC2 core peptide with microsome fraction of human-colon-carcinoma-LS174T-cells"Biochem J. 347. 535-542 (2000)
[文献書誌] Kang Y, et al.: "Increased expression after X-irradiation of MUC1 in cultured human colon carcinoma HT-29 cells"Jpn J Cancer Res.. 91. 324-330 (2000)
[文献書誌] Vestergaard C. et al.: "Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopi dermatitis-like lesions"J Clin Invest. 104. 1097-1105 (2000)
[文献書誌] Nagata K. et al.: "Redistribution of selectin counter-ligands induced by cytokines"Int Immunol.. 12. 487-492 (2000)
[文献書誌] Kimura T. et al.: "Epitope mapping of monoclonal antibodies specific for a macrophage lectin : a calcium-dependent epitope is in the carbohydrate recognition domain"Mol Immunol.. 37. 151-160 (2000)

2001 年度 実績報告書

膵臓がん肝転移モデルの設立と治療薬開発への応用

研究代表者

入村 達郎 東京大学, 大学院・薬学系研究科, 教授 (80092146)

研究成果

[文献書誌] Kato K. et al.: "Distinct Orders of GalNAc Incorporation into a Peptide with Consecutive Threonines"Biochem Biophys Res Commun.. 287. 110-115 (2001)

[文献書誌] Kato K. et al.: "N-acetylgalactosamine incorporation into a peptide containing consecutive threonine residues by UDP-N-acetyl-D-galactosamlnide : polypeptide N-acetylgalactosaminyltransferases"Glycobiology. 11. 812-829 (2001)

[文献書誌] Togayachi A. et al.: "Molecular cloning and characterization of UDP-GlcNAc : Lactosylceramide B1, 3-N-Acetylgalucosaminyltransferase (B3Gn-T5), an essential enzyme for the expression of HNK-1 and Lewix X epitopes on glycolipids"J Biol Chem.. 276. 22032-22040 (2001)

[文献書誌] Yim M. et al.: "Mutated plant lectin library useful to identify different cells"Proc Nat Acad Sci USA. 98. 2222-2225 (2001)

[文献書誌] Shirota K. et al.: "Anti-metastatic effect of the sialyl lewis-x analog GSC-150 on the human colon carcinoma derived cell line KM12-HX in the mouse"Biol Pharm Bull.. 24. 316-319 (2001)

[文献書誌] Kawamoto T, et al.: "Expression of MUC1 mucins with sialylated carbohydrates at the deepest invasding sites correlates with post-surgical prognosis of pT2 carcinoma of the galbladder"Clin Cancer Res. 7. 1333-1342 (2001)

[文献書誌] Amano J. et al.: "Intestinal epithelial cells express and secrete the CD43 glycoform that contains core 2 σ-glycans"Microbes and Infect. 3. 723-728 (2001)

[文献書誌] Uwatoku R. et al.: "Kupffer cell-mediated recruitment of rat dendritic cells to the liver : roles of N-acetylgaractosamine-specific sger recerptors"Gasteroenterology. 121. 1460-1472 (2001)

[文献書誌] Morimoto M. et al.: "Fibroblast migratory factor derived from mouse colon carcinoma cells : potential roles of fibronectin in tumor stroma formation"J Cell Biochem.. 80. 635-646 (2001)

[文献書誌] Denda-Nagai K. et al.: "MUC1 in carcinoma-host interactions"Giycoconjugate J. 17. 649-658 (2000)

[文献書誌] Denda-Nagai K. et al.: "Absence of correlation of MUC1 expression to malignant behavior of renal cell carcinoma in experimental systems"Clin Exp Metastasis. 18. 71-81 (2000)

[文献書誌] Kusaka Y. et al.: "Vital immunostaining of human gastric and colorectal cancer grafted into nude mice ; a preclinical assessment of a potential adjunct to videoendoscopy"J Gastroenterol. 35. 748-752 (2000)

[文献書誌] Chun K-H. et al.: "Involvement of cytokines in the skin-to-lymph node trafficking of cells of the monocyte-macrophage lineage expressing a C-type lectin"Int Immunol.. 12. 1695-1703 (2000)

[文献書誌] Ichii S, et al.: "Initial steps in lymph node metastasis formation in an experimental system : possible involvement of recognition by macrophage C-type lectins"Cancer Immunol Immunother. 49. 1-9 (2000)

[文献書誌] Chun K-H. et al.: "Migration of dermal cells expressing a macrophage C-type lectin during the sensitization phase of delayed-type hypersensitivity"J Leukocyte Biol.. 68. 471-478 (2000)

[文献書誌] Ota M, et al.: "Involvement of cell surface glycans in adhesion of human colon carcinoma cells to liver tissue in a frozen section assay : role of endo-b-galactosidase-sensitive structures"Cancer Res.. 60. 5261-5268 (2000)

[文献書誌] Koike J, et al.: "Density-dependent induction of TNF-a release from human monocytes by immobilized P-selectin"FEBS Lett. 477. 84-88 (2000)

[文献書誌] Iida S, et al.: "Order and maximum incorporation of N-acetyl-D-galactosamine into threonine residues of MUC2 core peptide with microsome fraction of human-colon-carcinoma-LS174T-cells"Biochem J. 347. 535-542 (2000)

[文献書誌] Kang Y, et al.: "Increased expression after X-irradiation of MUC1 in cultured human colon carcinoma HT-29 cells"Jpn J Cancer Res.. 91. 324-330 (2000)

[文献書誌] Vestergaard C. et al.: "Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopi dermatitis-like lesions"J Clin Invest. 104. 1097-1105 (2000)

[文献書誌] Nagata K. et al.: "Redistribution of selectin counter-ligands induced by cytokines"Int Immunol.. 12. 487-492 (2000)

[文献書誌] Kimura T. et al.: "Epitope mapping of monoclonal antibodies specific for a macrophage lectin : a calcium-dependent epitope is in the carbohydrate recognition domain"Mol Immunol.. 37. 151-160 (2000)

2001 年度実績報告書

入村達郎東京大学, 大学院・薬学系研究科, 教授 (80092146)