Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts
Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts
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DOI：
10.1136/gut.2004.048926
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发表时间：
2005-05-01
期刊：
影响因子：
24.5
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Min, Y;Adachi, Y;Imai, K
背景与目的：胰岛素样生长因子(IGF)I受体(IGF-ir)信号通路在许多肿瘤的致癌和增殖中是必需的，但在胃癌中这一信号通路尚未得到详细研究。我们以前已经证明使用表达显性阴性(DN)IGF-ir的重组腺病毒治疗结直肠癌、胰腺癌和肺癌是成功的。在这项研究中，我们试图更好地剖析IGF-ir在胃癌进展中的作用，并确定IGF-ir靶向腺病毒是否具有潜在的有效治疗胃癌的作用。方法：我们在培养的胃癌细胞中评价IGF-ir配体对胃癌细胞增殖和存活的影响。然后，研究了表达截短型IGF-ir(482和950个氨基酸，IGF-ir/dN)的重组腺病毒对人胃癌移植瘤的治疗作用。我们研究了IGF-ir/dN在信号传导阻断、生长、诱导细胞凋亡和体内治疗效果等方面的作用。IGF-ir/dN的表达抑制了体内和体外的致瘤性，并上调了应激源诱导的细胞凋亡。IGF-ir/dN可阻断IGF-I、IGF-II和DES(1-3)IGF-I诱导的Akt-1激活，但不能阻断胰岛素诱导的Akt-1激活。IGF-ir/dN的表达增加放化疗诱导的细胞凋亡，IGF-ir/dN联合化疗对小鼠肿瘤有很好的治疗作用。结论：IGF-ir参与了人胃癌生存和细胞生长的调控，有望成为良好的分子治疗靶点。因此，腺病毒-IGF-ir/dN可能对胃癌有治疗作用。
Background and aims: Insulin-like growth factor (IGF) I receptor (IGF-Ir) signalling is required for carcinogenicity and proliferation of many tumours but this pathway has not been studied in detail in gastric cancer. We have previously shown successful therapy for colorectal, pancreatic, and lung cancer using recombinant adenoviruses expressing dominant negative (dn) IGF-Ir. In this study, we sought to better dissect the role of IGF-Ir on progression of gastric cancer and determine whether IGF-Ir targeted adenoviruses represent potentially effective therapeutics for human gastric cancer.Methods: We assessed the effect of IGF-Ir ligands on proliferation and survival in gastric cancer cells in culture. Then, recombinant adenoviruses expressing truncated IGF-Ir (482 and 950 amino acids long, IGF-Ir/dn) that function as dn inhibitors were studied in the treatment of human gastric cancer xenografts. We characterised the effects of IGF-Ir/dn on signalling blockade, growth, apoptosis induction, and in vivo therapeutic efficacy.Results: IGF-Ir signalling promoted tumour growth and survival in gastric cancer. IGF-Ir/dn expression suppressed tumorigenicity both in vitro and in vivo and upregulated stressor induced apoptosis. IGF-Ir/dn blocked Akt-1 activation induced by IGF-I, IGF-II, and des(1-3)IGF-I, but not by insulin. IGF-Ir/dn expression increased radiation and chemotherapy induced apoptosis and the combination of IGF-Ir/dn and chemotherapy was very effective against tumours in mice. In an intraperitoneal model, IGF-Ir/dn therapy also suppressed peritoneal dissemination.Conclusions: IGF-Ir is involved in the regulation of survival and cell growth in human gastric cancer and may be a good molecular therapeutic target. Adenovirus-IGF-Ir/dn may thus have therapeutic use in gastric cancer.