Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models
Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models
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DOI：
10.3892/or.2015.4191
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发表时间：
2015-10-01
期刊：
影响因子：
4.2
通讯作者：
Yang, Seung-Ho
中科院分区：
文献类型：
--
作者：
Jun, Kyong-Hwa;Lee, Jung Eun;Yang, Seung-Ho
胃癌是全球癌症相关死亡的第二大常见原因。脑转移是胃癌的罕见并发症，但目前尚无针对胃癌脑转移的标准治疗方法。我们试图识别预测脑转移的生物学标记，并研究如何调节这些标记。我们对新诊断的胃癌患者在随访期间发生脑转移进行了病例对照研究。这些患者与晚期胃癌但无脑转移迹象的患者进行比较。采用免疫组化方法分析E-cadherin、N-cadherin、MSS1、claudin-3、claudin-4、Glut1、clusterin、ITGB4、血管内皮生长因子（VEGF）、表皮生长因子受体（EGFR）、p53的表达。病例组VEGF表达有升高趋势（33.3% vs. 0%, p=0.055）。中位生存期与血管浸润（12个月vs. 33个月，p=0.008）和N-cadherin表达（36个月vs. 12个月，p=0.027）显著相关。我们还研究了二甲双胍对荷瘤小鼠模型的影响。与对照组相比，二甲双胍治疗组VEGF表达降低，E-cadherin表达升高。二甲双胍组间充质标志物MMP9表达降低。进展期胃癌脑转移与VEGF表达相关。二甲双胍治疗可能有助于通过降低VEGF表达和阻断上皮细胞到间质细胞的转化来调节转移能力。
Gastric cancer is the second most common cause of cancer-related death worldwide. Although brain metastasis is a rare complication of gastric cancer, no standard therapy for gastric cancer brain metastasis has been established. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate such markers. A case-control study of patients newly diagnosed with gastric cancer who had developed brain metastasis during follow-up, was conducted. These patients were compared with patients who had advanced gastric cancer but no evidence of brain metastasis. Immunohistochemistry was used to analyze the expression of E-cadherin, N-cadherin, MSS1, claudin-3, claudin-4, Glut1, clusterin, ITGB4, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and p53. The expression of VEGF tended to be higher in the case group (33.3 vs. 0%, p=0.055). Median survival was significantly correlated with vascular invasion (12 vs. 33 months, p=0.008) and N-cadherin expression (36 vs. 12 months, p=0.027). We also investigated the effects of metformin in tumor-bearing mouse models. VEGF expression was decreased and E-cadherin increased in the metformin-treated group when compared with the control group. The expression of the mesenchymal marker MMP9 was decreased in the metformin-treated group. Brain metastasis of advanced gastric cancer was associated with the expression of VEGF. Metformin treatment may be useful for modulating the metastatic capacity by reducing VEGF expression and blocking epithelial-to-mesenchymal transition.