Treatment of pancreatic cancer by HGF antagonist, NK4, through new drug delivery system. -Approach from bench to practice

HGF 拮抗剂 NK4 通过新的药物输送系统治疗胰腺癌。

• 批准号: 13470257
• 负责人: TANAKA Masao
• 金额: $ 9.09万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470257/
• 关键词: Pancreatic cancer; HGF; NK4; Gene therapy; Angiogenesis inhibitor; MK4

Hepatocyte growth factor(HGF) is involved in malignant behavior of pancreatic cancer as a major mediator in tumor-stromal interaction through enhancing tumor invasion and metastasis. NK4, a four kringle fragment of HGF, functions as both an HGF-antagonist and an angiogenesis inhibitor. In this series of the experiments, we have clearly indicated that NK4 could be a promising molecule for gene therapy for pancreatic cancer. Documented results are as follows.1.In vitro experiments showed that all of eight human pancreatic cancer cells expressed c-Met/HGF receptor at varying level. HGF strongly stimulated migration and invasion of these cells. Recombinant NK4 abolished the increased invasion of pancreatic cancer cells. (Br J Cancer,2001) 2.Intraperitoneal administration of recombinant NK4 inhibited the growth, invasion, and metastasis of human pancreatic cancer implanted into the pancreas of nude mice. NK4 prolonged survival time of mice. (Cancer Res,2001). 3.Adenovirally-mediated transfe … More r of NK4(Ad-NK4) markedly inhibited scattering and invasion of pancreatic cancer cells. Furthermore, Ad-NK4 significantly inhibited the growth of tumors subcutaneously transplanted to nude mice. (Clin Exp Metastas,2001). 4.Growth of pancreatic cancer cells genetically engineered to secrete NK4 were significantly inhibited in both the orthotopic implantation and liver metastasis models. The anti-tumor effect is mainly obtained by NK4's function as an angiogenesis inhibitor rather than as an HGF antagonist. (Clin Cancer Res,2002). 5.Weekly intraperitoneal injection of Ad-NK4 Suppress the development of tumor nodules in a nude mouse peritoneal dissemination model and survival of the AD-NK4-treated mice was significantly imporoved. (Cancer Gene Therapy,2002). 6.For the development of new local delivery system, NK4-transduced oral mucosal epithelial cell(OMEC) sheet was made. NK4 secreted from OMEC sheet suppressed fibroblast-induced invasion of pancreatic cancer cells. NK4-sheets inhibited both angiogenesis and growth in vivo. (Clin Cancer Res,2003) Less

肝细胞生长因子（HGF）作为肿瘤间质相互作用的主要介质，通过促进肿瘤的侵袭和转移，参与胰腺癌的恶性行为。NK 4是HGF的四个kringle片段，既作为HGF拮抗剂又作为血管生成抑制剂。在这一系列的实验中，我们已经清楚地表明，NK 4可能是一个有前途的分子的基因治疗胰腺癌。实验结果如下：1.体外实验表明，8株人胰腺癌细胞均表达c-Met/HGF受体，但表达水平不同。HGF强烈刺激这些细胞的迁移和侵袭。重组NK 4消除了胰腺癌细胞的侵袭增加。(Br J Cancer，2001）2.腹膜内施用重组NK 4抑制植入裸鼠胰腺的人胰腺癌的生长、侵袭和转移。NK 4能延长小鼠的存活时间。（Cancer Res，2001）。3.腺病毒介导的转染 ...更多信息 NK 4的r（Ad-NK 4）能明显抑制胰腺癌细胞的扩散和侵袭。Ad-NK 4对裸鼠皮下移植瘤的生长有明显的抑制作用。(Clin Exp Metastas，2001）。4.在原位移植和肝转移模型中，经基因工程改造以分泌NK 4的胰腺癌细胞的生长均受到显著抑制。NK 4的抗肿瘤作用主要是通过其作为血管生成抑制剂而不是作为HGF拮抗剂的功能获得的。(Clin Cancer Res，2002）。5.每周腹腔注射一次Ad-NK 4可抑制裸鼠腹膜播散模型中肿瘤结节的形成，并显著提高小鼠的生存率。（Cancer Gene Therapy，2002）。6.为了开发新的局部给药系统，制备了NK 4转导的口腔粘膜上皮细胞（OMEC）片。从OMEC片层分泌的NK 4抑制成纤维细胞诱导的胰腺癌细胞的侵袭。NK 4-片层在体内抑制血管生成和生长。(Clin癌症研究，2003年）减

项目成果

Maehara et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br J Cancer. 84. 864-873 (2001)

Maehara 等人：“NK4 是 HGF 的四环拮抗剂，可抑制人胰腺癌细胞的扩散和侵袭”Br J Cancer。

Kuba K et al.: "HGF/NK4, a four-kirngle antagonist of hepatocyte growth factor is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice."Cancer Res.. 60. 6737-6743 (2000)

Kuba K 等人：“HGF/NK4 是肝细胞生长因子的四环拮抗剂，是一种血管生成抑制剂，可抑制小鼠肿瘤生长和转移。”Cancer Res.. 60. 6737-6743 (2000)

Qian LW et al.: "Radiation stimulates HGF receptor/e-Met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells."Int.J Cancer. 104(5). 5

Qian LW 等人：“辐射刺激 HGF 受体/e-Met 表达，通过上调胰腺癌细胞中的受体酪氨酸磷酸化和 MAP 激酶活性，导致细胞对 HGF 刺激的反应放大。”Int.J Cancer。

Saimura et al.: "Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4"Clinical Cancer Research. 8(10). 3243-3249 (2002)

Saimura 等人：“通过基因工程改造分泌 NK4 的 SUIT-2 胰腺癌细胞通过抑制血管生成来抑制肿瘤”临床癌症研究。

Tomioka et al.: "Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res. 61. 7518-7524 (2001)

Tomioka 等人：“NK4 在原位小鼠模型中抑制人胰腺癌细胞的生长、侵袭和转移”Cancer Res。