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Activation mutations in EGF receptor kinase have the advantages of cell physiology in the bronchiolar region : Implication of anti-apoptotic signals and lung tumorigenesis and metastasis.

EGF受体激酶的激活突变具有细支气管区域细胞生理学的优势：抗凋亡信号和肺肿瘤发生和转移的意义。

基本信息

批准号：
17390240
负责人：
NUKIWA Toshihiro
金额：
$ 9.66万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Backgrounds : The evolving concept of molecular targeting drugs has revolutionized the treatment of cancer. The first success of imatinib targeting the chimera protein of Bcr-abl in hematologic malignancies is followed by drugs for solid tumors, gefitinib or erlotinib, targeting the activation form of EGFR kinase (either deletion or L858R mutation). The latter is unique in facts that (1)Rthe mutation is specific for lung adenocarcinoma, (2)resulting in high affinity for ATP and anti-apoptosis, and (3) somatic but high incidence in far-east Orientals. We hypothesized that this specific EGFR mutation is selected because of the advantages in the respiratory bronchiolar regions.Methods : We used PC9 (EGFR deletion type), 11-18 (EGFR L858R) and A549 (EGFR wild type) cell lines and prepared COS-7 cells with EGFR/wt, EGFR/del, EGFR/L858R. Western blot analysis for in vitro signaling, and in vivo metastatic model using nude mice were performed. Expression microarray (Affymetrix U133 plus 2.0) … More analysis were conducted using 3 cell lines.Results : 1. In vitro signaling revealed that (1) while PC9 is constitutively active in usual FCS medium, 11-18 or COS-7 showed phosphorylation in Tyr1068 only after the addition of EGF after overnight starvation. (2) The pEGFR/Tyr1068 was detected in the order of COS-7/EGFR wt> COS-7/EGFR del>COS-7.2. PC9 (1O'6 cells) administered in the cervical vein resulted in tumors only in the lung in 2 months. Micro-metastatic lesions in the bronchiolar region were found using PC9 labeled with Cell Tracker 1 week after administration.3. Microarray expression analysis of PC9, 11-18, and A549 cell lines revealed two characteristic patterns: (1) PC9=11-18 > A549 (ARHGAP29 etc) or PC9=11-18 < A549 (DKK1 etc). (2) PC9 > 11-18=A549 (FOX03A etc) or PC9 < 11-18=A549 (catenin α 1 etc).Conclusion : Specific EGFR activation mutation showed distinct patterns of phosphrylation signaling. In vivo micro-metastasis was seen in the bronchiolar regions. Two characteristic patterns in the microarray expression analysis using PC9, 11-18, and A549 indicated the possible difference in the EGFR signaling and biological outcome. Less

研究背景：分子靶向药物的概念不断发展，给癌症的治疗带来了革命性的变化。伊马替尼靶向Bcr-abl嵌合蛋白在血液恶性肿瘤中的首次成功，随后是针对实体瘤的药物，吉非替尼或厄洛替尼，靶向EGFR激酶的活化形式（缺失或L 858 R突变）。后者的独特之处在于：（1）Rthe突变是肺腺癌的特异性突变，（2）导致对ATP的高亲和力和抗凋亡，（3）体细胞突变，但在远东东方人中发生率较高。方法：采用PC 9（EGFR缺失型）、11-18（EGFR L 858 R）和A549（EGFR野生型）细胞系，制备EGFR/wt、EGFR/del、EGFR/L 858 R的COS-7细胞。对体外信号传导和使用裸鼠的体内转移模型进行蛋白质印迹分析。表达微阵列（Affytron U133 plus 2.0） ...更多信息结果：1.对3种细胞系进行了分析。体外信号转导显示：（1）虽然PC 9在通常的FCS培养基中具有组成型活性，但11-18或COS-7仅在过夜饥饿后加入EGF后才显示Tyr 1068的磷酸化。(2)pEGFR/Tyr 1068的检测顺序为COS-7/EGFR wt> COS-7/EGFR del>COS-7.2。在颈静脉中施用的PC 9（10 - 6个细胞）在2个月内仅在肺中产生肿瘤。给药后1周，用细胞追踪器标记的PC 9在细支气管区发现微转移灶. PC 9、11-18和A549细胞系的微阵列表达分析揭示了两种特征模式：（1）PC 9 =11-18 > A549（ARHGAP 29等）或PC 9 =11-18 < A549（DKK 1等）。(2)PC 9> 11-18=A549（FOX 03 A等）或PC 9 < 11-18=A549（catenin α 1等）。体内微转移见于细支气管区。使用PC 9、11-18和A549的微阵列表达分析中的两个特征模式表明EGFR信号传导和生物学结果的可能差异。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gene mutations in lung cancer: promising predictive factors for the success of molecular therapy.

DOI：
10.1371/journal.pmed.0020013
发表时间：
2005-01
期刊：
PLoS medicine
影响因子：
15.8
作者：
Inoue A;Nukiwa T
通讯作者：
Nukiwa T

呼吸の事典(40 呼吸と肺癌)

呼吸百科全书（40种呼吸与肺癌）

DOI：
发表时间：
2006
期刊：
影响因子：
0
作者：
貫和敏博(共著;有田秀穂編集)
通讯作者：
有田秀穂編集)

Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis.

DOI：
10.1016/j.ymthe.2005.02.019
发表时间：
2005-07
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Masaki Watanabe;M. Ebina;F. Orson;A. Nakamura;Kazuo Kubota;D. Koinuma;Kenichi Akiyama;M. Maemondo;S. Okouchi;M. Tahara;Kunio Matsumoto;Toshikazu Nakamura;T. Nukiwa
通讯作者：
Masaki Watanabe;M. Ebina;F. Orson;A. Nakamura;Kazuo Kubota;D. Koinuma;Kenichi Akiyama;M. Maemondo;S. Okouchi;M. Tahara;Kunio Matsumoto;Toshikazu Nakamura;T. Nukiwa

Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors

DOI：
10.1002/eji.200535549
发表时间：
2006-04
期刊：
European Journal of Immunology
影响因子：
5.4
作者：
M. Nukiwa;S. Andarini;J. Zaini;H. Xin;M. Kanehira;Takuji Suzuki;T. Fukuhara;H. Mizuguchi;T. Hayakawa
通讯作者：
M. Nukiwa;S. Andarini;J. Zaini;H. Xin;M. Kanehira;Takuji Suzuki;T. Fukuhara;H. Mizuguchi;T. Hayakawa

Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis