Activation of signal transduction pathway by aberration of oncogenes : comprehensive analysis and application for multi-molecular targeting therapy

• Project/Area Number: 20590351
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: Jichi Medical University
• Principal Investigator: DOBASHI Yoh Jichi Medical University, 医学部, 准教授 (90231456)
• Co-Investigator(Kenkyū-buntansha): ENDO Syunsuke 自治医科大学, 医学部, 教授 (10245037) ; YANAGAWA Takashi (KITAGAWA Masatoshi) 群馬大学, 医学部, 助教 (50294971) ; 柳川 天志 群馬大学, 医学部, 助教 (40400725)
• Co-Investigator(Renkei-kenkyūsha): MATSUBARA Hirochika 山梨大学, 医学部・附属病院, 助手 (00374166) ; SATO Eiiti 山梨大学, 医学工学総合研究部, 助教 (80293455) ; OOI Akishi 金沢大学, 医学系研究科, 教授 (50160411)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 呼吸器 / 縦隔 / 肺癌 / EGFR / 遺伝子変異 / Akt / mTOR / S6 kinase / 遺伝子増幅 / ポリソミー / 骨軟部肉腫 / リンパ節転移 / 骨軟部腫瘍 / シグナル伝達 / Pirh2 / 分子標的療法

Research Abstract

The involvement of epidermal growth factor receptor (EGFR) cascade was analyzed in lung carcinomas and in soft tissue sarcoma. Overexpression/activation of EGFR was observed in 37% and constitutive activation of cascade was found in 11%. Mutation of EGFR was observed in 24% and associated with cell proliferation and metastasis. Increase of AKT genes were found in 45% with reciprocal relation against increase of EGFR gene. In sarcoma, mTOR activation was associated with morphogenesis in tumors of neural and skeletal muscle origin.

Research Products

• [Journal Article] Paradigm of kinase-driven pathway downstream of EGFR/Akt in human lung carcinomas. (2011)
  • Author(s): Dobashi, Y., Suzuki, S., Kimura, M., Matsubara, H., Tsubochi, H., Imoto, I., Ooi, A.
  • Journal Title: Hum. Pathol. 42(2) Pages: 214-26
  • Peer Reviewed
• [Journal Article] Paradigm of kinase-driven pathway downstream of EGFR/Akt in human lung carcinomas. (2011)
  • Author(s): Dobashi, Y.
  • Journal Title: Hum.Pathol. Volume: 42(2) Pages: 214-226
  • Peer Reviewed
• [Journal Article] Kinase-driven pathways downstream of EGFR in human lung carcinomas : perspectives on molecular targeting therapy. (2011)
  • Author(s): Dobashi, Y.
  • Journal Title: Front Biosci Volume: 16 Pages: 1714-32
  • Peer Reviewed
• [Journal Article] Kinase-driven pathways downstream of EGFR in human lung carcinomas : perspectives on molecular targeting therapy. (2010)
  • Author(s): Dobashi, Y., Koyama, S., Kanai, Y., Tetsuka, K.
  • Journal Title: Front Biosci. Landmark 16 Pages: 1714-1732
  • Peer Reviewed
• [Journal Article] Gene Amplification of ERBB2 and EGFR in adenocarcinoma in situ and intramucosal adenocarcinoma of Barrett's esophagus. (2010)
  • Author(s): Ooi, A., Zen, Y., Ninomiya, I., Tajiri, Y., Suzuki1, S., Kobayashi, H., Imoto, I., Dobashi, Y.
  • Journal Title: Pathol Int. 60(6) Pages: 466-471
  • NAID: 10029332233
  • Peer Reviewed
• [Journal Article] Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer. (2010)
  • Author(s): Suzuki, S., Dobashi, Y., Hatakeyama, Y., Tajiri, R., Fujimura, T., Heldin, C.H., Ooi, A.
  • Journal Title: BMC Cancer 10 Pages: 659-659
  • NAID: 120003913338
  • Peer Reviewed
• [Journal Article] Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer. (2010)
  • Author(s): Suzuki, S.
  • Journal Title: BMC Cancer Volume: 10 Pages: 659-659
  • Peer Reviewed
• [Journal Article] Critical and diverse involvement of the Akt/mTOR signaling in human lung carcinomas. (2009)
  • Author(s): Dobashi, Y., Suzuki, S., Matsubara, H., Kimura, M., Endo, S., Ooi, A.
  • Journal Title: Cancer 115(1) Pages: 107-118
  • Peer Reviewed
• [Journal Article] Gene amplification of Myc and its coamplification with ERBB2 and EGFR in gallbladder adenocarcinomas. (2009)
  • Author(s): Ooi, A., Suzuki, S., Nakazawa, K., Itakura, J., Imoto, I., Nakamura, H., Dobashi, Y.
  • Journal Title: Anticancer Res. 29(1) Pages: 19-26
  • Peer Reviewed
• [Journal Article] High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers. (2009)
  • Author(s): Shimada, M., Kitagawa, K., Dobashi, Y., Isobe, T., Hattori, T., Uchida, C., Abe, K., Kotake, Y., Oda, T., Suzuki., Hashimoto, K., Kitagawa, M.
  • Journal Title: Cancer Science 100(5) Pages: 866-872
  • NAID: 10025145601
  • Peer Reviewed
• [Journal Article] EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors. (2009)
  • Author(s): Dobashi, Y., Suzuki, S., Sato, E., Hamada, Y., Yanagawa, T., Ooi, A.
  • Journal Title: Mod.Pathol. 22(10) Pages: 1328-1340
  • Peer Reviewed
• [Journal Article] Polyamine-rich food decreases age-associated pathology and mortality in aged mice. (2009)
  • Author(s): Soda, K., Dobashi, Y., Kano, Y., Tsujinaka, S., Konishi, F.
  • Journal Title: Exp.Gerontol. 44(11) Pages: 727-732
  • Peer Reviewed
• [Journal Article] High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers (2009)
  • Author(s): Shimada, M.
  • Journal Title: Cancer Science 100(5) Pages: 866-872
  • Peer Reviewed
• [Journal Article] EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors (2009)
  • Author(s): Dobashi, Y.
  • Journal Title: Mod.Pathol. 22(10) Pages: 1328-1340
  • Peer Reviewed
• [Journal Article] Polyamine-rich food decreases age-associated pathology and mortality in aged mice (2009)
  • Author(s): Soda, K
  • Journal Title: Exp.Gerontol. 44(11) Pages: 727-732
  • Peer Reviewed
• [Journal Article] Critical and diverse involvement of the Akt/mTOR signaling in human lung carcinomas. (2009)
  • Author(s): Dobashi, Y.
  • Journal Title: Cancer 115(1) Pages: 107-18
  • Peer Reviewed
• [Journal Article] Prognostic significance of 18F-FDG uptake in primary osteosarcoma after but not before chemotherapy : a possible association with autocrine motility factor/phosphoglucose isomerase expression. (2008)
  • Author(s): Sato, J., Yanagawa, T., Dobashi, Y., Yamaji, T., Takagishi, K., Watanabe, H.
  • Journal Title: Clin.Exp.Metasta. 25(4) Pages: 427-435
  • Peer Reviewed
• [Journal Article] Prognostic significance of 18F-FDG uptake in primary osteosarcoma after but not before chemotherapy : a possible association with autocrine motility factor/phosphoglucose isomerase expression. (2008)
  • Author(s): Sato, J.
  • Journal Title: Clin. Exp. Metasta. 25(4) Pages: 427-435
  • Peer Reviewed
• [Journal Article] Regression of multiple duodenal hyperplastic polyps following Helicobacter pylori eradication.
  • Author(s): Ugajin T
  • Journal Title: Digestive Endoscopy. Volume: 23(4)(In press)
  • Peer Reviewed
• [Journal Article] Gene Amplification of ERBB2 and EGFR in adenocarcinoma in situ and intramucosal adenocarcinoma of Barrett's esophagus
  • Author(s): Ooi, A.
  • Journal Title: Pathol.Int. (In press)
  • NAID: 10029332233
  • Peer Reviewed
• [Journal Article] Gene amplification of Myc and its coamplification with ERBB2 and EG FR in gallbladder adenocarcinomas.
  • Author(s): Ooi, A.
  • Journal Title: Anticancer Ees. (In press. )
  • Peer Reviewed
• [Journal Article] High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers.
  • Author(s): Shimada, M.
  • Journal Title: Cancer Science (In press. )
  • Peer Reviewed
• [Presentation] 唾液腺癌におけるEGFR,HER2遺伝子増幅および蛋白過剰発現 (2011)
  • Author(s): 鈴木潮人、湊宏、土橋洋、田尻亮輔、大井章史
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-04-30
• [Presentation] FISHを用いた大腸癌におけるEGFR遺伝子の増幅の検討 (2011)
  • Author(s): 大井章史、鈴木潮人、田尻亮輔、土橋洋、源利成
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-04-29
• [Presentation] 肺癌におけるエフェクター分子Aktの活性化と遺伝子変化 (2011)
  • Author(s): 土橋洋、鈴木潮人、椙村春彦、山田茂樹、大井章史
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-04-28
• [Presentation] Paradigm of kinase-driven pathway downstream of EGFR/Akt in human lung carcinomas. (2010)
  • Author(s): 土橋洋、鈴木潮人、大井章史
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] Paradigm of kinase-driven pathway downstream Of EGFR/Akt in human lung carcinomas. (2010)
  • Author(s): 土橋洋
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] 肺癌におけるEGFR/Akt/mTOR/S6 kinase経路の機能的関与の多様性 (2010)
  • Author(s): 土橋洋、鈴木潮人、山田茂樹、大井章史
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-27
• [Presentation] バレット腺癌におけるERBB2及びEGFRの過剰発現と遺伝子増幅-FISHを用いた検討 (2010)
  • Author(s): 大井章史、土橋洋、鈴木潮人、田尻亮輔、全陽
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-27
• [Presentation] 胃癌の新生血管に関する臨床病理学的検討 (2010)
  • Author(s): 鈴木潮人、土橋洋、畠山弥生、田尻亮輔、大井章史
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-27
• [Presentation] パレット腺癌におけるERBB2及びEGFRの過剰発現と遺伝子増幅-FISHを用いた検討 (2010)
  • Author(s): 大井章史
  • Organizer: 第99回日本病理学会総会発表
  • Place of Presentation: 東京
  • Year and Date: 2010-04-27
• [Presentation] 肺癌におけるEGFRの異常とその下流因子の関与 (2009)
  • Author(s): 土橋洋、鈴木潮人、大井章史
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-02
• [Presentation] Pirh2はp27のユビキリンリガーゼとして人の癌の悪性度に関与する (2009)
  • Author(s): 北川雅敏、島田真衣、土橋洋、服部隆行、神武洋二郎、橋本賢二、北川恭子
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-02
• [Presentation] 間葉系腫瘍におけるEGFRカスケードの関与 (2009)
  • Author(s): 土橋洋、鈴木潮人、山田茂樹、大井章史
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-03
• [Presentation] 間葉系腫瘍におけるEGFRカスケードの関与 (2009)
  • Author(s): 土橋洋
  • Organizer: 第98回日本病理学会総会発表
  • Place of Presentation: 京都
  • Year and Date: 2009-05-03
• [Presentation] 肺癌患者血性中の腫瘍特異的自己抗体としての抗AMF抗体の有用性 (2009)
  • Author(s): 小林信、影山泰平、松本俊英、長塩亮、土橋洋、佐藤雄一、岡安勲
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-02
• [Presentation] 乳癌におけるMYC遺伝子の増幅の検討 (2009)
  • Author(s): 大井章史、幾川恵吏、鈴木潮人、土橋洋、全陽
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-01
• [Presentation] 胃癌におけるVEGF, PDGFシグナル経路の病理学的検討 (2009)
  • Author(s): 鈴木潮人、土橋洋、畠山弥生、田尻亮輔、大井章史
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-01
• [Presentation] 乳癌におけるMYC遺伝子の増幅の検討 (2009)
  • Author(s): 大井章史
  • Organizer: 第98回日本病理学会総会発表
  • Place of Presentation: 京都
  • Year and Date: 2009-05-01
• [Presentation] 自治医科大学さいたま医療センターでのベセスダシステムによる子宮頸部細胞診報告の現状. (2008)
  • Author(s): 河野 哲也
  • Organizer: 第47回日本臨床細胞学会秋期大会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-14
• [Presentation] 活性変異型PDGFR-β(D849N)の血管新生増強効果. (2008)
  • Author(s): 鈴木 潮人
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] 胆嚢癌におけるMyc遺伝子増幅、特にERBB2及びEGFR遺伝子との同時増幅について. (2008)
  • Author(s): 大井 章史
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] 胆嚢癌におけるMyc遺伝子増幅、特にERBB2及びEGFR遺伝子との同時増幅について (2008)
  • Author(s): 大井章史、鈴木潮人、井本逸勢、土橋洋
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-03
• [Presentation] 活性変異型PDGFR-β(D849N)の血管新生増強効果 (2008)
  • Author(s): 鈴木潮人、土橋洋
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-02
• [Presentation] 左顎下腺に発生した多形腺腫由来粘表皮癌の一例. (2008)
  • Author(s): 森野 咲子
  • Organizer: 第49回日本臨床細胞学会
  • Place of Presentation: 東京
  • Year and Date: 2008-06-07
• [Presentation] PDGFR-βの活性化型変異D849NはB16メラノーマの増殖を促進する (2008)
  • Author(s): 鈴木潮人、土橋洋、大井章史
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-16
• [Presentation] PDGFR-βの活性化型変異D849NはB16メラノーマの増殖を促進する. (2008)
  • Author(s): 鈴木 潮人
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-16
• [Presentation] ヒト肺癌におけるEGFRの遺伝子異常、下流因子の活性化の意義とその分子病理学的意義 (2008)
  • Author(s): 土橋洋、鈴木潮人、大井章史
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-15
• [Presentation] ヒト肺癌におけるEGFRの遺伝子異常,下流因子の活性化の意義とその分子病理学的意義. (2008)
  • Author(s): 土橋 洋
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-15
• [Book] 細胞傷害と細胞増殖、シンプル病理学第6版(笹野公伸、岡田保典、安井弥編)東京 (2010)
  • Author(s): 土橋洋
  • Publisher: 南江堂
• [Book] Molecular targeting therapy in Bone and Soft Tissue Tumors : Perspectives on this new mode of therapy. In Soft Tissue cancers.N.Y. U.S.A. (2008)
  • Author(s): Dobashi, Y., Kimura, M., Sato, E., Hamada, Y., Ooi, A.
  • Publisher: Nova Science Publisher LtD
• [Book] リン酸化研究の歴史と病理からのアプローチ.病理と臨床.26(8) (2008)
  • Author(s): 木村麻衣子、土橋洋
• [Book] In Soft Tissue cancers. “Molecular targeting therapy in Bone and Soft Tissue Tumors : Perspectives on this new mode of therapy. " (2008)
  • Author(s): Dobashi, Y.
  • Total Pages: 36
  • Publisher: Nova Science Publisher LtD.
• [Book] 病理と臨床. “リン酸化研究の歴史と病理からのアプローチ. " (2008)
  • Author(s): 木村麻衣子
  • Total Pages: 2
  • Publisher: 文光堂
• [Remarks] ホームページ等