Basic and clinical research on growth and metastasis of human osteosarcoma

人骨肉瘤生长和转移的基础与临床研究

基本信息

批准号：
11307026
负责人：
WADA Takuro
金额：
$ 25.15万
依托单位：
SAPPORO MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307026/
关键词：
Osteosarcoma tumor associated antigen costimulatory signal tumor immunity Erb2 receptor protein Vascular endothelial growth factor EWS-ETS fusion gene expression cloning ヒト骨肉種骨肉種腫瘍抗原接着分子導入細胞ワクチン BMP-2 EWS-Flil G-CSF 骨肉種転移

项目摘要

Human osteosarcom associated antigens were identified by using SEREX (serological identification of antigen by recombinant expression cloning) method. Eight candidate genes were identified. They included the genes encoding procollagen type 1 and c-myc binding protein homologue.Human osteosarcoma associated antigen was identified with expression cloning method. The osteosarcoma cell line (OS2000) and its cytotoxic T-lymphocyte clone (CTL) were used. An HLA-A24 and B55 restricted molecule encoded by 1, 9O0-base pair gene was identified.B7-1 gene, a member of B7 costimulatory family, was introduced to rat osteosarcoma cells in vivo by using adenovirus vector. Curative immunity against primary osteosarcoma and systemic immunity against pulmonary metastasis was observed. B7-1a molecule induced the most efficacious costimulatory signal among B7 family members.Expression of ErbB2 gene was compared between the primary and pulmonary metastatic lesions of the same osteosarcoma patients. Loss of … More ErbB2 expression was noted in 14 of 19 patients as the primary tumor became metastatic. In patients with high-grade osteosarcoma without metastatic disease at presentation and treated with surgery and chemotherapy, the presence of increased level of ErbB2 in tumor cells is associated with a significantly increased probability of event-free and overall survival.Vascular endothelial growth factor (VEGF) expression in untreated ostesarcoma is predictive of pulmonary metastasis and poor prognosis in patients who underwent aggressive therapy. In addition, the pre-therapeutic serum VEGF level reflects tne angiogenic property of primary tumor and has a predictive value on early disease relapse of osteosarcoma.To identify downstream targets of EWS-ETS fusion protein, we introduced EWS-ETS into a human fibrosarcoma cell line. Tenascin-C is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal EWS-ETS. As Tenascin-C expression is involved in the invasive and malignant phenotype, the oncogenic effect of EWS-ETS may be mediated in part by upregulating of Tenascin-C expression. Less

采用SEREX（重组表达克隆血清学鉴定抗原）方法鉴定了人骨肉瘤相关抗原，其中包括编码1型前胶原和c-myc结合蛋白同源物的基因。使用骨肉瘤细胞系（OS2000）及其细胞毒性T淋巴细胞克隆（CTL）。鉴定出1, 9O0碱基对基因编码的限制性分子。利用腺病毒载体将B7共刺激家族成员B7-1基因导入体内大鼠骨肉瘤细胞中，获得针对原发性骨肉瘤的治愈性免疫和针对肺转移的全身免疫。观察到B7-1a分子在B7家族成员中诱导最有效的共刺激信号。比较原发灶和肺转移灶之间ErbB2基因的表达。在 19 名患者中，有 14 名患者发现 ErbB2 表达缺失，因为原发肿瘤发生转移，而在就诊时没有转移性疾病且接受手术和化疗治疗的高级别骨肉瘤患者中，ErbB2 水平升高。肿瘤细胞中的血管内皮生长因子 (VEGF) 表达与无事件生存率和总生存率显着增加相关。未经治疗的骨肉瘤中血管内皮生长因子 (VEGF) 的表达可预测肺转移和此外，治疗前血清VEGF水平反映了原发肿瘤的血管生成特性，对骨肉瘤的早期疾病复发具有预测价值。为了确定EWS-ETS融合蛋白的下游靶标。将 EWS-ETS 引入人纤维肉瘤细胞系中，表达 EWS-ETS 的细胞中的 Tenascin-C 诱导水平显着高于表达正常 EWS-ETS As 的细胞。 Tenascin-C 表达涉及侵袭性和恶性表型，EWS-ETS 的致癌作用可能部分是通过 Tenascin-C 表达的上调介导的。