Mechanism of development and progression of gastrointestinal cancer by analysis of insulirrlike growth factor system and extracelluar matrix degrading enzymes

胰岛素样生长因子系统和细胞外基质降解酶分析胃肠癌发生发展机制

• 批准号: 18390220
• 负责人: YAMAMOTO Hiroyuki
• 金额: $ 10.78万
• 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 (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390220/
• 关键词: insulin-like growth factor; extracellular matrix degrading enzyme; gastrointestinal cancer; microsatellite instability; IGF- 1 receptor; dominant negative; tyrosine kinase inhibitor; Akt; 細胞外基質分解酵素; ERK; IGF-I receptor; Akt-1; bystander効果

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. The association between the expression of IGF-IR and IGF-II ligand and prognosis was investigate in surgically resected esophageal squamous cell carcinoma (ESCC). We then assessed the therapeutic effect of blocking IGF-IR signaling using dominant negative IGF-IR (IGF-IR/dn) in ESCC in vitro. Expression of IGF-IR and IGF-II were detected in 60 and 50% of tumors, respectively, and were associated with the progression and recurrence. Patients with tumors expressing both IGF-IR and IGF-II had the worst prognosis in both single and multivariate analysis. IGF-IR/dn suppressed proliferation and motility as well as upregulating chemotherapy-induced apoptosis through blocking ligand-induced Akt activation. Detection of IGF-IR/IGF-II in ESCC may be useful for the prediction of recurrence and poor prognosis and for selecting patients for IGF-IR-targeted the … More rapy.We assessed the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541 on signal transduction, proliferation, survival, and migration in gastrointestinal cancer cells. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by IGFs, but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose dependent manner in all cell lines. The drug inhibited tumor as a single agent and when combined with stressors, up-regulated apoptosis in a dose dependent fashion, and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. Thus, NVP-AEW541 may have significant therapeutic utility in human gastrointestinal carcinomas, both alone and incombination with chemotherapy. Less

胰岛素样生长因子（IGF）-I受体（IGF-IR）信号传导是胃肠道癌的致癌性和增殖所必需的。本研究旨在探讨手术切除的食管鳞状细胞癌（ESCC）中胰岛素样生长因子-IR和胰岛素样生长因子-II配体（IGF-II ligand）的表达与预后的关系。然后，我们评估了在体外使用显性负性IGF-IR（IGF-IR/dn）阻断IGF-IR信号传导在ESCC中的治疗效果。IGF-IR和IGF-II的表达分别在60%和50%的肿瘤中检测到，并且与进展和复发相关。在单因素和多因素分析中，肿瘤同时表达IGF-IR和IGF-II的患者预后最差。IGF-IR/dn通过阻断配体诱导的Akt激活抑制细胞增殖和运动，并上调化疗诱导的细胞凋亡。IGF-IR/IGF-II在食管鳞癌中的检测可能有助于预测复发和不良预后，并有助于选择患者接受IGF-IR靶向治疗。 ...更多信息 我们评估了一种新的IGF-IR酪氨酸激酶抑制剂NVP-AEW 541对胃肠道癌细胞的信号转导、增殖、存活和迁移的影响。在体外和裸鼠异种移植物中研究了NVP-AEW 541单独和与化疗的作用。我们还分析了NVP-AEW 541对胰岛素信号和IGF-IR与胰岛素受体之间的杂合受体形成的影响。NVP-AEW 541阻断IGF-IR的自磷酸化以及IGFs对Akt和ERK的激活，但不阻断胰岛素对Akt和ERK的激活。NVP-AEW 541在所有细胞系中以剂量依赖性方式抑制体外增殖和致瘤性。该药物作为单一药剂抑制肿瘤，并且当与应激物组合时，以剂量依赖性方式上调细胞凋亡，并抑制移动性。NVP-AEW 541增强了化疗对体外生长和诱导凋亡的影响。此外，NVP-AEW 541和化疗的组合对小鼠的肿瘤非常有效。因此，NVP-AEW 541可能在人胃肠道癌中具有显著的治疗效用，无论是单独使用还是与化疗联合使用。少

项目成果

Insulin-like growth factor-I receptor as a candidate for a novel molecular target in the gastrointestinal cancers

胰岛素样生长因子-I 受体作为胃肠癌新分子靶标的候选者

• 发表时间: 2006
• 期刊: Digest. Endoscopy. 18
• 作者: Yasushi;Adachi
• 通讯作者: Adachi

Epigenetic downregulation of the receptor tyrosine kinase EphA6 in human colorectal cancers

人类结直肠癌中受体酪氨酸激酶 EphA6 的表观遗传下调

• 发表时间: 2007
• 作者: Nobuki;Miyamoto;Tadateru Maehata
• 通讯作者: Tadateru Maehata

Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis

• DOI: 10.1016/j.ejca.2006.01.061
• 发表时间: 2006-09-01
• 期刊: EUROPEAN JOURNAL OF CANCER
• 影响因子: 8.4
• 作者: Nosho, Katsuhiko;Yamamoto, Hiroyuki;Shinomura, Yasuhisa
• 通讯作者: Shinomura, Yasuhisa

Differential expression of angiogenesis-related genes in human gastric cancers with and those without high-frequency microsatenite instabihty

存在和不存在高频微卫星不稳定性的人胃癌中血管生成相关基因的差异表达

• 发表时间: 2007
• 作者: Hiroyuki;Yamamoto;Nobuki Miyamoto
• 通讯作者: Nobuki Miyamoto

Insulin-like growth factor-I receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma

• DOI: 10.1093/carcin/bgl247
• 发表时间: 2007-05-01
• 期刊: CARCINOGENESIS
• 影响因子: 4.7
• 作者: Imsumran, Arisa;Adachi, Yasushi;Imai, Kohzoh
• 通讯作者: Imai, Kohzoh