Insulin-like growth factor-1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus
Insulin-like growth factor-1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus
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DOI：
10.1002/ijc.25196
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发表时间：
2010-10-15
影响因子：
6.4
通讯作者：
Yekebas, Emre F.
中科院分区：
文献类型：
--
作者：
Kalinina, Tatyana;Bockhorn, Maximilian;Yekebas, Emre F.
胰岛素样生长因子1受体（IGF-1R）和人表皮生长因子受体2（HER2）受体的表达已被发现是肿瘤发生的关键调节因子。我们研究的目的是确定 IGF-1R 在食管癌中的预后意义，并确定 α-IR3 和 Herceptin (TM) 抗体靶向 IGF-1R 和 HER2 对食管癌细胞体外增殖的影响。使用包含 234 个食管癌标本（133 个腺癌和 101 个鳞状细胞癌）的组织微阵列分析 IGF-1R 表达和临床病理学相关性。使用独特的人食管癌细胞系 Pt1590 和 LN1590 评估与赫赛汀 (TM) 和 alpha-IR3 阻断相关的增殖变化。通过Western blotting分析IGF-1R和HER2的表达水平、参与激活途径的下游信号蛋白的激活和磷酸化状态。在检查的 234 个食管肿瘤中，有 121 个（52%）检测到 IGF-1R 过度表达。在 87 个 HER2 阳性肿瘤亚组中，93.1% 显示 IGF-1R 一致过表达。 IGF-1R 被确定为与腺癌总生存率降低相关的变量 (p = 0.05)，但与鳞状细胞癌无关。赫赛汀 (TM) 和 α-IR3 的组合在抑制体外增殖方面比单独使用任一药物治疗更有效 (p < 0.01)。这与 HER2 和 IGF-1R 蛋白水平的降低以及 Akt 和 MAP 激酶磷酸化的抑制有关。 IGF-1R 表达可用作食管腺癌的新型预后标志物。 IGF-1R 和 HER2 抗体联合治疗可能成为食管腺癌有价值且有效的治疗选择。
Insulin-like growth factor-1 receptor (IGF-1R) and human epidermal growth factor receptor-2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF-1R in esophageal cancer and to determine the effect of IGF-1R and HER2 targeting with alpha-IR3 and Herceptin (TM) antibodies on the proliferation of esophageal cancer cells in vitro. IGF-1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin (TM) and alpha-IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF-1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF-1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2-positive tumors, 93.1% showed concordant overexpression for IGF-1R. IGF-1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin (TM) and alpha-IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF-1R protein levels and suppression of Akt- and MAP kinase phosphorylation. IGF-1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF-1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma.