Adenovirus-mediated Smad4 gene transfer inhibit.s tumor growth and metastasis of human pancreatic carcinoma

腺病毒介导的Smad4基因转移抑制人胰腺癌的肿瘤生长和转移

• 批准号: 14571211
• 负责人: NAGAI Eishi
• 金额: $ 2.5万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571211/
• 关键词: Pancreatic cancer; Smad 4; Gene therapy; Inhibition of angiogenesis

Pancreatic cancer is one, of the most difficult neoplasms to treat curatively, because of its highly invasive and metastatic potential. We previously generated an antagonist. for HOF which played an important role in invasion and metastasis of human pancreatic cancer. This HGF-antagonist., NK4 has competitive inhibitory effects on interaction between HGF and C-MET receptor. Furthermore, NK4 inhibits proliferation and migration of distinct. type of endotbelial cells stimulated by angiogenic factor. In our privios study, adnovirus-mediated NK4 gene therapy suppressed the growth, invasiveness and metastasis of human pancreatic cancer cell lines with high expression of c-MET. However, there are a few pancreatic cancer cell lines with low level of c-MET expression, so we focused on Smad 4/DPC4. SMAD4 is a critical cofactor in signal transduction pathways activated in response to transforming growth factor-beta (TGF-beta)-related ligands, regulating cell growth and differentiation. Smad4 has been reported to express the inhibitory effects of on pancreatic tumour invasion and angiogenesis. Adenovirus mediated gene transfer in a panel of SMAD4 homozygouscleleted human pancreatic tumor cell lines should restore SMAD4 protein ex-pression and function. Thus adenovirus mediated Smad 4 gene therapy may be another attractive option for the treatment of pancreatic cancer. We are now preparing recombinat aclenovirus for cell growth and invasiveness of pancreatic cancer cell lines. The tumor growth of adenovirus-NK4 infected pancreatic cancer cells in nude mice will be analyzed.

胰腺癌是最难治愈的肿瘤之一，因为它具有高度的侵袭性和转移性。我们之前生成了一个拮抗剂。霍夫在胰腺癌的侵袭和转移中起重要作用。这种HGF拮抗剂，NK 4对HGF与C-MET受体的相互作用具有竞争性抑制作用。此外，NK 4抑制不同细胞的增殖和迁移。血管生成因子刺激的内皮细胞类型。在我们的前期研究中，腺病毒介导的NK 4基因治疗抑制了高表达c-MET的人胰腺癌细胞系的生长、侵袭和转移。然而，有一些胰腺癌细胞系具有低水平的c-MET表达，因此我们将重点放在Smad 4/DPC 4上。SMAD 4是信号转导途径中的关键辅因子，其响应于转化生长因子-β（TGF-β）相关配体而被激活，调节细胞生长和分化。据报道，Smad 4表达对胰腺肿瘤侵袭和血管生成的抑制作用。腺病毒介导的SMAD 4基因转移在一组SMAD 4纯合子筛选的人胰腺癌细胞系中可恢复SMAD 4蛋白的表达和功能。因此腺病毒介导的Smad 4基因治疗可能是胰腺癌治疗的另一个有吸引力的选择。我们现在正在制备用于胰腺癌细胞系的细胞生长和侵袭力的重组腺病毒。将分析腺病毒-NK 4感染的胰腺癌细胞在裸鼠中的肿瘤生长。