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Aberrant activation of signal transduction pathways regulating cell proliieration in human slid tumors. Molecular-pathological analysis and clinical application of molecular targeting therapy.

调节人类肿瘤细胞增殖的信号转导途径的异常激活。

基本信息

批准号：
18590327
负责人：
DOBASHI Yoh
金额：
$ 2.47万
依托单位：
Jichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

During this term, analyses for aberration of oncogenes, such as EGFR (Epidermal growth factor receptor), HER-2 (human EGFR-2), c-myc and their signal pathways were performed in bone and soft tissue sarcomas (BSTS), gastric and lung carcinomas. We have clarified and reported the followings.1. In esophageal carcinomas, overexpression of EGFR was observed 50%, and amplification was in 14.2% (Int. J. Cancer, 2006). And also, in BSTS, EGFR overexpression was in 22.6%, and amplification was in 12.9%, but increase of EGFR gene, including that at low level, was noted up to 39% (Hum. Pathol, 2007). Thus, molecular targeting therapy against EGFR could be indicative for those malignancies2. Point mutation of EGFR was found in 29% of lung adenocarcinomas and, in those cases, Akt was specifically activated downstream of EGFR. In contrast, lung carcinoma with EGFR amplification, stat-3 was activated as a re sponsible effector molecule (Mod. Pathol. 2005). In BSTS, although point mutation was observed in 13%, Akt was not necessarily activated, unlike the cases in lung carcinomas (Hum. Pathol, 2007).3. Topoisomerase IIa gene was also amplified in 3% of gastric carcinomas, but they were always associated with HER-2 gene amplification (Hum. Pathol. 2006).4. c-myc was overexpressed in 16% and amplified in 3% of gastric carcinomas, and c-myc was co-amplified with EGFR or HER-2 in 5% of the cases (Mod. Pathol. 2007).5. Invasion-related protein, autocrine motility factor (AMF) was expressed in 72.5% of the BSTS, and in 67% of lung carcinomas. The tumor expressing high level of mRNA and secreting AMF at high amount were found to be the cases showing high metastatic probability. Furthermore, in osteosarcoma, high level of AMF expression correlated with high level of FDG-PET signals and was a marker of post-operative metastasis (Clin. Exp. Meta. 2007).

在此期间，对骨和软组织肉瘤（BSTS）、胃癌和肺癌中的癌基因，如EGFR（表皮生长因子受体）、HER-2（人EGFR-2）、c-myc及其信号通路的畸变进行了分析。我们已经澄清并报告了以下内容。1.在食管癌中，观察到50%的EGFR过表达，14.2%的EGFR扩增（Int. J. Cancer，2006）。在BSTS中，EGFR过表达率为22.6%，扩增率为12.9%，但EGFR基因表达增加（包括低水平）高达39%（P < 0.01）。Pathol，2007）。因此，针对EGFR的分子靶向治疗可以指示这些恶性肿瘤2。29%的肺腺癌中发现EGFR点突变，在这些病例中，Akt在EGFR下游特异性激活。相比之下，在EGFR扩增的肺癌中，stat-3被激活为反应效应分子（Mod. Pathol. 2005年）。在BSTS中，尽管在13%中观察到点突变，但Akt不一定被激活，这与肺癌中的情况不同（1999年）。Pathol，2007）。拓扑异构酶Ⅱ a基因在胃癌中也有3%的扩增，但它们总是与HER-2基因扩增相关（P < 0.05）。Pathol. 2006年）。c-myc在16%的胃癌中过表达，在3%的胃癌中扩增，并且在5%的病例中c-myc与EGFR或HER-2共扩增（Mod.Pathol.2004）。2007年）。自分泌运动因子（AMF）在BSTS中的表达率为72.5%，在肺癌中的表达率为67%。高表达AMF mRNA和高分泌AMF的肿瘤是转移可能性高的病例。此外，在骨肉瘤中，高水平AMF表达与高水平FDG-PET信号相关，并且是术后转移的标志物（Clin. Exp. Meta. 2007年）。