2001 Fiscal Year Annual Research Report

悪性骨軟部腫瘍の浸潤、転移に関わるシグナル伝達分子を標的とした新しい治療法の開発

Research Project

Project/Area Number	12557125
Research Institution	Kyushu University
Principal Investigator	岩本幸英九州大学, 大学院・医学研究院, 教授 (00213322)
Co-Investigator(Kenkyū-buntansha)	田仲和宏九州大学, 医学部・附属病院, 助手 (10274458) 小田義直九州大学, 大学院・医学研究院, 講師 (70291515)
Keywords	悪性骨軟部腫瘍 / 骨肉腫 / 基底膜浸潤 / 転移 / 細胞骨格 / シグナル伝達
Research Abstract	悪性骨軟部腫瘍患者の死因のほとんどは転移である。転移に際し腫瘍細胞は血管内皮細胞下の基底膜を浸潤、破壊するが、この基底膜浸潤は、転移成立の多段階プロセスのなかで最も重要と考えられている。我々は、この基底膜浸潤のモデルであるinvasion assayを開発し、基底膜浸潤の分子機構を解析し、その抑制法の開発に向けた研究を推進してきた。その結果、悪性腫瘍細胞の基底膜への接着、酵素的破壊、運動に関与する遺伝子は、接着分子や細胞骨格関連分子からのシグナル伝達により発現が一挙に変化し、浸潤、転移を惹起している可能性が示唆された。一方、近年、Rhoファミリー、インテグリンという浸潤、転移に関与する2つの主要な分子が注目され、その下流のシグナル伝達経路の解析が進んでいるが、両者の相互関係は全く明らかにされていない。今回の研究の目的は、インテグリンとRhoのシグナル伝達経路とクロストークの詳細な検討を行い、その経路の中で細胞の転移形質を一度に抑制しうる最も重要な因子を分子標的とし同定し、その分子標的に対する有効な抑制法を検討し、悪性骨軟部腫瘍の浸潤、転移の新しい治療法の開発につなげることである。我々はすでに、細胞内cAMP濃度を上昇させることで、ヒト線維肉腫細胞HT1080の浸潤、転移が抑制できることを報告している。本年度は、この現象の分子機構について解析した。その結果、cAMP誘導体を作用させると、PKAを介してRho活性化が抑制された。これがアクチンストレスファイバー形成の抑制を引き起こし、さらにFAKのリン酸化も抑制し、浸潤能が低下させることが判明した。また、悪性組織性組織球腫の臨床サンプルにおいて、FAKのリン酸化と腫瘍再発に関連がある可能性を見いだした。

Research Products
(21 results)

All Other

All Publications (21 results)

[Publications] Matsumoto Y, et al.: "Small GTP-binding Protein, Rho, Both Increased and Decreased Cellular Motility, Activation of Matrix Metalloproteinase 2 and Invasion of Human Osteosarcoma Cells"Jpn. J. Cancer Res.. 92. 429-438 (2001)
[Publications] Matsumoto Y, et al.: "Downregtlation ant forcec expression of EWS-Fli I fusion gene re stits in changes in the expression of C(1) regulatory genes"Brit. J. Cancer. 84. 768-775 (2001)
[Publications] Saito T, et al.: "Expression of intercellular adhesion molecules in epith elioid sarcoma and malignant rhabdoid tumor"Pathol. Int.. 51. 532-542 (2001)
[Publications] Oda Y, et al.: "Pleomorphic Leiomyosarcoma-Clinicopathologic and immunohistochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibros histiocytoma"Am. J. Surg. Pathol. 25. 1030-1038 (2001)
[Publications] Saito T, et al.: "β-catcin nuclear expression corrclatcs with cyclin DI overexpression in sporadic desmoid tumors"J. Pathol.. 195. 222-228 (2001)
[Publications] Naka T, et al.: "Immunohistochemical analysis of E-cadherin, alpha-, beta-, gamma-cetenins, and neural cell adhesion moleculc(NCAM) in chordoma"J. Clin. Pathol.. 54. 945-950 (2001)
[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated liposarcoma : Polymerize chain reaction-restriction fragment length polymorphism analysis"Am. J. Clin. Pathol.. 115. 235-242 (2001)
[Publications] Saito T, et al.: "E-Cadherin Gene Mutations Frequently Occur in Synovial Sarcoma as a Determinant of Histologica Features"Am. J. Pathol.. 159. 2117-2124 (2001)
[Publications] Sakamoto A, et al.: "Immunoexpression of Neurofibromin, S-100 Protein and Leu-7, and Mutation Analysis of the NF1 Gene at Codon 1423 in Osteofibros Dysplasia"Hum. Pathol.. 32. 1245-1251 (2001)
[Publications] Sakamoto A, et al.: "H-, K-and N-ras Gene Mutation in Atypical Fibroxanthoma and Malignant fibrous Histiocytoma"Hum. Pathol.. 32. 1225-1231 (2001)
[Publications] Sakamoto A, et al.: "Immunoexpression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma"Mod. Pathol.. 14. 581-588 (2001)
[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated chondrosarcoma : Polymerase chain reaction-restriction fragment lengt polymorphism analysis of paraffin-embedded tissues"Mod. Pathol.. 14. 343-349 (2001)
[Publications] Oda Y, et al.: "Secondary malignant giant-cell tumor of bone. Molecular abnormalitiesof p53 and H-ras gene correlated with malignant transformation"Histopathology. 39. 629-637 (2001)
[Publications] Kinoshita Y, et al.: "Mutation of the p53 gene mutations in malignant rhabdoidtumors of soft part and kidney : Immunohistochemical and DNA direct sequence analysis"J. Cancer Res. Clin. Oncol.. 127. 351-358 (2001)
[Publications] Shiratsuhi H, et al.: "Cytokeratin sibunits of inclusion bodies in rhabdoid cells : Immunohistochemidal and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma"Int. J. Surg. Pathol.. 9. 37-48 (2001)
[Publications] Miyajima K, et al.: "Relative quantitation of p53 and MDM2 gene expression in leiomyo sarcoma ; rear-time semi-quantitative reverse transcription-polymerase chain reaction"Cancer Letters. 164. 177-188 (2001)
[Publications] Watanabe T, et al.: "Malignantperipheraln ervesheathtumorarising within neuro fibromaAn immuno histochemical analysis in the comparison between benign and malignant components"J. Clin. Pathol.. 54. 631-636 (2001)
[Publications] Adachi T, et al.: "Adachi T, Oda Y, Sakamoto A, Saito T, Tamiya S, Masuda K, Tsuneyoshi Mlmmunoreactivily of p53. mdrn2 and p21/WAF1 in dedifferentiated liposarcoma : special emphasis on the distinet immunophenotype of the Well-differentiated component"Int. J. Surg. Pathol.. 9. 99-109 (2001)
[Publications] 岩本幸英(分担執筆): "今日の治療指針2001年度版-私はこう治療している-"医学書院. 1566 (2001)
[Publications] 播广谷勝三, 岩本幸英(分担執筆): "今日の処方,第3版"南江堂. 935 (2001)
[Publications] 松田秀一, 岩本幸英(分担執筆): "新OS NOW 新世代の整形外科手術,No.13高齢者に対する整形外科手術-より高い機能を求めて"Medical View社. 192 (2001)

2001 Fiscal Year Annual Research Report

悪性骨軟部腫瘍の浸潤、転移に関わるシグナル伝達分子を標的とした新しい治療法の開発

Principal Investigator

岩本 幸英 九州大学, 大学院・医学研究院, 教授 (00213322)

Research Products

[Publications] Matsumoto Y, et al.: "Small GTP-binding Protein, Rho, Both Increased and Decreased Cellular Motility, Activation of Matrix Metalloproteinase 2 and Invasion of Human Osteosarcoma Cells"Jpn. J. Cancer Res.. 92. 429-438 (2001)

[Publications] Matsumoto Y, et al.: "Downregtlation ant forcec expression of EWS-Fli I fusion gene re stits in changes in the expression of C(1) regulatory genes"Brit. J. Cancer. 84. 768-775 (2001)

[Publications] Saito T, et al.: "Expression of intercellular adhesion molecules in epith elioid sarcoma and malignant rhabdoid tumor"Pathol. Int.. 51. 532-542 (2001)

[Publications] Oda Y, et al.: "Pleomorphic Leiomyosarcoma-Clinicopathologic and immunohistochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibros histiocytoma"Am. J. Surg. Pathol. 25. 1030-1038 (2001)

[Publications] Saito T, et al.: "β-catcin nuclear expression corrclatcs with cyclin DI overexpression in sporadic desmoid tumors"J. Pathol.. 195. 222-228 (2001)

[Publications] Naka T, et al.: "Immunohistochemical analysis of E-cadherin, alpha-, beta-, gamma-cetenins, and neural cell adhesion moleculc(NCAM) in chordoma"J. Clin. Pathol.. 54. 945-950 (2001)

[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated liposarcoma : Polymerize chain reaction-restriction fragment length polymorphism analysis"Am. J. Clin. Pathol.. 115. 235-242 (2001)

[Publications] Saito T, et al.: "E-Cadherin Gene Mutations Frequently Occur in Synovial Sarcoma as a Determinant of Histologica Features"Am. J. Pathol.. 159. 2117-2124 (2001)

[Publications] Sakamoto A, et al.: "Immunoexpression of Neurofibromin, S-100 Protein and Leu-7, and Mutation Analysis of the NF1 Gene at Codon 1423 in Osteofibros Dysplasia"Hum. Pathol.. 32. 1245-1251 (2001)

[Publications] Sakamoto A, et al.: "H-, K-and N-ras Gene Mutation in Atypical Fibroxanthoma and Malignant fibrous Histiocytoma"Hum. Pathol.. 32. 1225-1231 (2001)

[Publications] Sakamoto A, et al.: "Immunoexpression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma"Mod. Pathol.. 14. 581-588 (2001)

[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated chondrosarcoma : Polymerase chain reaction-restriction fragment lengt polymorphism analysis of paraffin-embedded tissues"Mod. Pathol.. 14. 343-349 (2001)

[Publications] Oda Y, et al.: "Secondary malignant giant-cell tumor of bone. Molecular abnormalitiesof p53 and H-ras gene correlated with malignant transformation"Histopathology. 39. 629-637 (2001)

[Publications] Kinoshita Y, et al.: "Mutation of the p53 gene mutations in malignant rhabdoidtumors of soft part and kidney : Immunohistochemical and DNA direct sequence analysis"J. Cancer Res. Clin. Oncol.. 127. 351-358 (2001)

[Publications] Shiratsuhi H, et al.: "Cytokeratin sibunits of inclusion bodies in rhabdoid cells : Immunohistochemidal and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma"Int. J. Surg. Pathol.. 9. 37-48 (2001)

[Publications] Miyajima K, et al.: "Relative quantitation of p53 and MDM2 gene expression in leiomyo sarcoma ; rear-time semi-quantitative reverse transcription-polymerase chain reaction"Cancer Letters. 164. 177-188 (2001)

[Publications] Watanabe T, et al.: "Malignantperipheraln ervesheathtumorarising within neuro fibromaAn immuno histochemical analysis in the comparison between benign and malignant components"J. Clin. Pathol.. 54. 631-636 (2001)

[Publications] 岩本幸英(分担執筆): "今日の治療指針2001年度版-私はこう治療している-"医学書院. 1566 (2001)

[Publications] 播广谷勝三, 岩本幸英(分担執筆): "今日の処方,第3版"南江堂. 935 (2001)

[Publications] 松田秀一, 岩本幸英(分担執筆): "新OS NOW 新世代の整形外科手術,No.13高齢者に対する整形外科手術-より高い機能を求めて"Medical View社. 192 (2001)

岩本幸英九州大学, 大学院・医学研究院, 教授 (00213322)