Clinicopathological analysis of lung adenocarcinomas by EGFR gene mutation and gene expression analysis

• Project/Area Number: 18590321
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: The University of Tokyo
• Principal Investigator: OTA Satoshi The University of Tokyo, Graduate school of medicine, lecturer (90324342)
• Co-Investigator(Kenkyū-buntansha): FUKAYAMA Masashi The University of Tokyo, Graduate school of medicine, Professor (70281293) ; 後藤 明輝 東京大学, 大学院医学系研究科, 助手 (90317090)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: lung cancer / EGFR gene mutation / oncofetal protein GPC3 / 腫瘍

Research Abstract

Prognosis of lung adenocarcinomas is extremely poor. This project purpose is that the identification of the candidate molecules for molecularly-targeted drug by gene expression profile and immunohistochemical analyses.
1 Analyses of EGFR mutation and oncofetal protein GPC3 expression in lung adenocarcinomas: Recent studies including our reports have shown the expression of oncofetal protein GPC3 in neoplastic cells of Yolk sac tumor, choriocarcinoma, teratoma, hepatocellular carcinoma, and Wilm's tumor. Lung tissue specimens were retrieved from the file of the Department of Pathology, Tokyo University Hospital in 2005 and 2006. The 32 samples could be analyzed both with EGFR mutation and GPC3 immunostaining. EGFR mutation was detected in 11 cases of 32 cases (34%). GPC3 was positive in 8 cases, including 6 adenocarcinomas with mixed subtypes, one solid adenocarcinoma with mucin production, and well differentiated fetal adenocarcinoma. In 2 cases, both week GPC3 expression and EGFR mutat ion were detected. Gene expression profile revealed the expression of GPC3 in the one of 18 lung adenocarcinomas cell lines. Those results suggested the GPC3 expression in lung adenocarcinomas broadly indicated the fetal type adenocarcinomas and GPC3 is promising candidate for molecularly-targeted drug.
2 In human lung adenocarcinomas, recent important topic was the acquired resistance the EGFR kinase inhibitors, gefitinib and erlotinib. One of the candidates for alternative constitutive active signaling molecule is c-met, instead of EGFR pathway. Constitutive activation of c-Met was detected 5 out of 12 lung adenocarcinomas cell lines. The mechanisms c-Met overexpression were that either with or without gene amplification, ligand-independent and depends on cell-matrix adhesion.
3 Tumor hypoxia is associated with a malignant phenotype of cancer cells and poor patient prognosis. In the A549 lung adenocarcinomas cell line, hypoxia induced the cell motility and EGFR gene expression level EGFR inhibitor AG1478 completely inhibited the promotion of cell motility induced by hypoxia.

Research Products

• [Journal Article] Constitutive activation of c-Met overexpression and dependent on cel1-matrix adhesion in lung adenocarcinoma celllines. (2008)
  • Author(s): Nakamura Y, Matsubara D, Goto A, Ota S, Sachiko O, Ishikawa S, Aburatani H, Miyazawa K, Fukayama M, Niki T.
  • Journal Title: Cancer science 99 Pages: 14-22
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Constitutive activation of c-Met is correlated with c-Met overexpression and dependent on cell-matrix adhesion in lung adenocarcinoma cell lines (2008)
  • Author(s): Nakamura Y, Matsubara D, Goto A, Ota S, Sachiko O, Ishikawa S, Aburatani H, Miyazawa K, Fukayama M, Niki T.
  • Journal Title: Cancer Sci 99 Pages: 14-22
  • NAID: 10024000720
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Constitutive activation of c-Met is correlated with c-Met overexpression and dependent on cell-matrix adhesion in lung adenocarcinoma cell lines. (2008)
  • Author(s): Nakamura Y, Matsubara D, Goto A, Ota S, Sachiko O, Ishikawa S, Aburatani H, Miyazawa K, Fukayama M, Niki T.
  • Journal Title: Cancer Science 99 Pages: 14-22
  • NAID: 10024000720
  • Peer Reviewed
• [Journal Article] Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway. (2007)
  • Author(s): Wang T, Niki T, Goto A, OtaS, Morikawa T, Nakamura Y, Ohara E, Ishikawa S, Aburatani H, Nakajima J, Fukayama M.
  • Journal Title: Cancer Science 98 Pages: 506-511
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway (2007)
  • Author(s): Wang T, Niki T, Goto A, Ota S, Morikawa T, Nakamura Y, Ohara E, Ishikawa S, Aburatani H, Nakajima J, Fukayama M.
  • Journal Title: Cancer Sci 98 Pages: 506-511
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway. (2007)
  • Author(s): Wang T, Niki T, Goto A, Ota S, Morikawa T, Nakamura Y, Ohara E, Ishikawa S, Aburatani H, Nakajima J, Fukayama M
  • Journal Title: Cancer science 98 Pages: 506-511