Tumor promotion effect by IL-1β gene transfer : Analysis of cancer-stromal interaction.

IL-1β 基因转移的肿瘤促进作用：癌症-基质相互作用的分析。

• 批准号: 11670563
• 负责人: SAIJO Yasuo
• 金额: $ 2.18万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670563/
• 关键词: lung cancer; gene thransfer; IL-1β; cancer-stromal interaction; HGF

Interleukin-1β (IL-1β) is a multifunctional and proinflamatory cytokine and affects nearly all cell type. In this study, we have constructed the retroviral vector expressing a hybrid gene of signal sequence and human IL-1β gene. Mouse Lewis lung carcinoma (LLC) cells were transduced with IL=1β gene (LLC/IL-1β). LLC/IL-1β accelerated tumor growth in mice despite of no change of growth property in vitro. Immunohistochemistry of CD31 in LLC/IL-1β tumor revealed hyper-neovascularization. LLC/IL-1β cells secreted larger amount of VEGF and MIP-2 whose one of main function is angigenesis. Moreover, LLC/IL-1β tumor contained over 4 times higher concentration of hepatocyte growth factor (HGF), although LLC/IL-1β cells itself did not secreted HGF in vitro. In situ hybridization of HGF mRNA demonstrated that stromal fibroblasts overexpressed HGF mRNA.An anti-angiogenic agent TNP-470 inhibited tumor growth of LLC/IL-1β cells. These results demonstrated that secreting IL-1β into tumor milieu induces several angiogenic factors from cancer and stromal cells and thus promotes tumor growth through neovascularization.

白细胞介素-1 β（IL-1β）是一种多功能的促炎细胞因子，几乎影响所有细胞类型。本研究构建了信号肽与人IL-1β基因杂交的逆转录病毒表达载体。用IL=1β基因（LLC/IL-1β）转导小鼠刘易斯肺癌（LLC）细胞。LLC/IL-1β促进小鼠肿瘤生长，但对肿瘤生长特性无明显影响。LLC/IL-1β肿瘤中CD 31的免疫组化显示过度新生血管形成。LLC/IL-1β细胞分泌大量VEGF和MIP-2，其主要功能之一是血管生成。此外，LLC/IL-1β肿瘤含有超过4倍浓度的肝细胞生长因子（HGF），尽管LLC/IL-1β细胞本身在体外不分泌HGF。原位杂交结果显示，间质成纤维细胞高表达HGF mRNA，抗血管生成剂TNP-470可抑制LLC/IL-1β细胞的肿瘤生长。这些结果表明，分泌IL-1β到肿瘤环境中诱导来自癌症和基质细胞的几种血管生成因子，从而通过新血管形成促进肿瘤生长。

项目成果

Masashi Tanaka, Yasuo Saijo, George Sato, Takuji Suzuki, Ryushi Tazawa, Ken Satoh, and Toshihiro Nukiwa.: "Induction of antitumor immunity by combined immunogene therapy using IL-2 and IL-12 in Low Antigenic Lewis Lung Carcinoma."Cancer Gene Therapy. 7. 1

Masashi Tanaka、Yasuo Saijo、George Sato、Takuji Suzuki、Ryushi Tazawa、Ken Satoh 和 Toshihiro Nukiwa。：“在低抗原性路易斯肺癌中使用 IL-2 和 IL-12 联合免疫基因疗法诱导抗肿瘤免疫。”癌症基因

Tanaka M,Narumi K,Isemura M,Abe M,Sato M,Saijo Y et al.: "Expression of the 37-kda laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis."Cancer Letters. 153. 161-167 (2000)

Tanaka M、Narumi K、Isemura M、Abe M、Sato M、Saijo Y 等人：“鼠肺肿瘤细胞中 37-kda 层粘连蛋白的表达与肿瘤血管生成相关。”《癌症快报》。

Saijo Y.et al.: "Autologous high killing cytotoxic T lymphocytes against human lung cancer are induced using IL-1β, IL-2, IL-4, and IL-6"Clinical Cancer Research. 5. 1203-1209 (1999)

Saijo Y.等人：“使用IL-1β、IL-2、IL-4和IL-6诱导针对人肺癌的自体高杀伤性细胞毒性T淋巴细胞”临床癌症研究5. 1203-1209 (1999)。

Tanaka M,Saijo Y,Sato G,Suzuki T,Tazawa R,Satoh K,Nukiwa T.: "Induction of antitumor immunity by combined immunogene therapy using IL-2 and IL-12 in low antigenic lewis lung carcinoma."Cancer Gene Therapy. 7. 1481-1490 (2000)

Tanaka M、Saijo Y、Sato G、Suzuki T、Tazawa R、Satoh K、Nukiwa T.：“在低抗原性刘易斯肺癌中使用 IL-2 和 IL-12 联合免疫基因治疗诱导抗肿瘤免疫。”癌症基因治疗

Takuji Suzuki, Yasuo Saijo, Masahito Ebina, Masahiro Yaekashiwa, Masayoshi Minegishi, Shigeru Tsuchiya, Tasuke Konno, Shuichi Ono, Yuji Matsumura, Shigefumi Fujimura, and Toshihiro Nukiwa: "Bilateral pneumothoraces with multiple bullae in a patient with b

Takuji Suzuki、Yasuo Saijo、Masahito Ebina、Maesahiro Yaekashiwa、Masayoshi Minegishi、Shigeru Tsuchiya、Tasuke Konno、Shuichi Ono、Yuji Matsumura、Shigefumi Fujimura 和 Toshihiro Nukiwa：“双侧气胸伴多发大疱的患者