Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance-Implications for IGF-II and IGF-IR-Targeted Therapy
Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance-Implications for IGF-II and IGF-IR-Targeted Therapy
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DOI：
10.1158/1078-0432.ccr-13-2735
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发表时间：
2014-05-15
影响因子：
11.5
通讯作者：
Cheung, Annie L. M.
中科院分区：
文献类型：
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作者：
Li, Bin;Tsao, Sai Wah;Cheung, Annie L. M.
目的：研究Id 1诱导的胰岛素样生长因子-II（IGF-II）在食管癌中的自分泌/内分泌作用，并评估IGF-II和IGF-I型受体（IGF-IR）靶向治疗的潜力。实验设计：基于抗体阵列的筛选用于鉴定Id 1过表达食管癌细胞差异分泌的生长因子。在体外和体内试验进行，以确认诱导IGF-II的Id 1，并研究IGF-II在促进食管癌进展的自分泌和内分泌作用。应用人食管癌组织芯片分析IGF-II的表达及其与Id 1和磷酸化AKT（p-AKT）的相关性。使用体内肿瘤异种移植物和实验性转移models.Results：Id 1过表达诱导IGF-II分泌，从而促进癌细胞增殖，生存，并通过自分泌方式激活AKT的侵袭，瘤内注射IGF-II抗体和腹腔注射cixutumumab（全人单克隆IGF-1 R抗体）的疗效进行了评估。在35例食管癌组织中有21例（60%）发现IGF-II过表达，并与Id 1和p-AKT上调相关。Id 1过表达的食管癌异种移植瘤分泌的IGF-II可以刺激远端食管肿瘤的生长，以及促进循环癌细胞的转移。以IGF-II和IGF-IR为靶点对小鼠肿瘤生长和转移有明显的抑制作用。Cixutumumab治疗增强了肿瘤异种移植物对氟尿嘧啶和顺铂的化疗敏感性。结论：Id 1-IGF-II-IGF-IR-AKT信号级联在食管癌进展中起重要作用。阻断IGF-II/IGF-IR信号传导在食管癌的管理中具有治疗潜力。(C)2014年AACR。
Purpose: To investigate the autocrine/endocrine role of Id1-induced insulin-like growth factor-II (IGF-II) in esophageal cancer, and evaluate the potential of IGF-II- and IGF-type I receptor (IGF-IR)-targeted therapies.Experimental Design: Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing esophageal cancer cells. In vitro and in vivo assays were performed to confirm the induction of IGF-II by Id1, and to study the autocrine and endocrine effects of IGF-II in promoting esophageal cancer progression. Human esophageal cancer tissue microarray was analyzed for overexpression of IGF-II and its correlation with that of Id1 and phosphorylated AKT (p-AKT). The efficacy of intratumorally injected IGF-II antibody and intraperitoneally injected cixutumumab (fully human monoclonal IGF-IR antibody) was evaluated using in vivo tumor xenograft and experimental metastasis models.Results: Id1 overexpression induced IGF-II secretion, which promoted cancer cell proliferation, survival, and invasion by activating AKT in an autocrine manner. Overexpression of IGF-II was found in 21 of 35 (60%) esophageal cancer tissues and was associated with upregulation of Id1 and p-AKT. IGF-II secreted by Id1-overexpressing esophageal cancer xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells. Targeting IGF-II and IGF-IR had significant suppressive effects on tumor growth and metastasis in mice. Cixutumumab treatment enhanced the chemosensitivity of tumor xenografts to fluorouracil and cisplatin.Conclusions: The Id1-IGF-II-IGF-IR-AKT signaling cascade plays an important role in esophageal cancer progression. Blockade of IGF-II/IGF-IR signaling has therapeutic potential in the management of esophageal cancer. (C) 2014 AACR.