Combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors for non-small cell lung cancers

使用转移抑制基因疗法和血管生成抑制剂联合治疗非小细胞肺癌

• 批准号: 16591400
• 负责人: HUANG Cheng-long
• 金额: $ 2.24万
• 依托单位: Kagawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591400/
• 关键词: tumor metastatic suppressor gene; metastasis; angiogenesis; angiogenesis inhibitor; gene therapy; adenoviral vector; spontaneous metastasis model; 血管新生限害剤

We constructed the spontaneous metastasis model using the inoculation of tumor cell lines or tumor tissues into nude mice. The comprehensive analysis of expressions of tumor metastatic suppressor genes and angiogenesis factors revealed a reduced MRP-1/CD9 expression, a reduced KAI1/CD82 expression, and a reduced E-cadherin expression to be associated with pulmonary metastases. Regarding angiogenesis factors, a VEGF-A expression and a interleukin-8 expression were associated with intratumoral angiogenesis. In lung cancers, the HGF-cMet pathway was associated with the tumor proliferation, but not with angiogenesis (Br J Cancer 2004). The comprehensive analyses of gene expressions using cDNA microarray assays have demonstrated that the MRP-1/CD9 gene transduction suppresses the Wnt signal pathways (Oncogene 2004) and a WAVE2 expression (Oncogene 2006). Furthermore, we found the Wnt1 expression to be associated with the intratumoral VEGF-A expression, and the Wnt5a expression to be associated with the stromal VEGF-A expression (J Clin Oncol 2005). The finding that the MRP-1/CD9 transduction induces the down-regulation of VEGF-A, one of a Wnt target, suggested the possibility of the synergic effect of the combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors. Therefore, we performed experimental studies on combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors using the spontaneous metastasis model of nude mice. The adenoviral transfection of MRP-1/CD9 and KAI1/CD82 suppressed pulmonary metastases of tumors, respectively. TNP-470 and CGS27023A, angiogenesis inhibitors, also suppressed pulmonary metastases. Although TNP-470 inhibited tumor growth, but it caused weight loss as a side effect. However, we could not find any synergic effects in various types of the combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors.

我们通过将肿瘤细胞系或肿瘤组织接种到裸鼠体内来构建自发转移模型。肿瘤转移抑制基因和血管生成因子表达的综合分析显示，MRP-1/CD 9表达降低，KAI 1/CD 82表达降低，E-cadherin表达降低与肺转移相关。关于血管生成因子，VEGF-A表达和白细胞介素-8表达与肿瘤内血管生成相关。在肺癌中，HGF-cMet途径与肿瘤增殖相关，但与血管生成无关（Br J Cancer 2004）。使用cDNA微阵列分析的基因表达的综合分析已经证明MRP-1/CD 9基因转导抑制Wnt信号通路（Oncogene 2004）和WAVE 2表达（Oncogene 2006）。此外，我们发现Wnt 1表达与肿瘤内VEGF-A表达相关，Wnt 5a表达与基质VEGF-A表达相关（J Clin Oncol 2005）。MRP-1/CD 9转导诱导Wnt靶点之一的VEGF-A下调的发现提示了使用转移抑制基因治疗和血管生成抑制剂的联合治疗的协同效应的可能性。因此，我们利用裸鼠自发转移模型进行了转移抑制基因治疗和血管生成抑制剂联合治疗的实验研究。腺病毒转染MRP-1/CD 9和KAI 1/CD 82分别抑制肿瘤的肺转移。血管生成抑制剂TNP-470和CGS 27023 A也抑制肺转移。虽然TNP-470抑制肿瘤生长，但它会引起体重减轻的副作用。然而，我们没有发现任何协同作用，在各种类型的联合治疗的转移抑制基因治疗和血管生成抑制剂。

项目成果

The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer ptatients

瘤内c-Met和基质肝细胞生长因子之间的肿瘤基质相互作用与非小细胞肺癌患者肿瘤生长和预后相关

• 发表时间: 2004
• 期刊: British Journal of Cancer 90
• 作者: Daiki Masuya;et al.
• 通讯作者: et al.

The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth faclorassociated with tumour growth and prognosis in non-small cell lung cancer patients

肿瘤内 c-Met 和基质肝细胞生长因子之间的肿瘤基质相互作用与非小细胞肺癌患者的肿瘤生长和预后相关

• 发表时间: 2004
• 期刊: British Journal of Cancer 90・8
• 作者: Daiki Masuya;et al.
• 通讯作者: et al.

Wnt5a expression is associated with the tumor proliferation and the stromal vascular endothelial growth factor - An expression in non-small-cell lung cancer

• DOI: 10.1200/jco.2005.02.2871
• 发表时间: 2005-12-01
• 期刊: JOURNAL OF CLINICAL ONCOLOGY
• 影响因子: 45.3
• 作者: Huang, CL;Liu, D;Ueno, M
• 通讯作者: Ueno, M

The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways

• DOI: 10.1002/path.1931
• 发表时间: 2006-04-01
• 期刊: JOURNAL OF PATHOLOGY
• 影响因子: 7.3
• 作者: Masuya, D;Huang, C;Sumitomo, S
• 通讯作者: Sumitomo, S

Expression of vascular endothelial growth factor-A and vascular endothelial growth factor-C as prognostic factors for non-small cell lung cancer.

• 发表时间: 2004-06
• 期刊: Medical science monitor : international medical journal of experimental and clinical research
• 作者: T. Nakashima;Cheng‐long Huang;Dage Liu;K. Kameyama;D. Masuya;M. Ueno;R. Haba;H. Yokomise