Overexpression of platelet-derived growth factor receptor α in endothelial cells of hepatocellular carcinoma associated with high metastatic potential
Overexpression of platelet-derived growth factor receptor α in endothelial cells of hepatocellular carcinoma associated with high metastatic potential
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DOI：
10.1158/1078-0432.ccr-05-0944
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发表时间：
2005-12-15
影响因子：
11.5
通讯作者：
Tang, ZY
中科院分区：
文献类型：
--
作者：
Zhang, T;Sun, HC;Tang, ZY
目的：关于肝细胞癌血管内皮异质性的信息很少。本研究的目的是鉴定高转移性肝细胞癌肿瘤内皮细胞中差异表达的基因。实验设计：采用缀合抗CD31抗体的磁珠从裸鼠不同转移潜能的肝细胞癌移植瘤中分离血管内皮细胞。使用cDNA微阵列比较不同内皮细胞的基因表达谱。通过逆转录PCR、实时PCR和免疫组织化学证实了上调基因。结果：cDNA微阵列分析揭示了从不同转移潜能的肝细胞癌中分离的内皮细胞中一致存在的7个基因的差异表达模式。血小板衍生生长因子受体a仅在高度转移性肝细胞癌的内皮细胞中过度表达，这一点通过逆转录PCR、实时PCR和免疫组织化学得到证实。口服 ST1571（甲磺酸伊马替尼或格列卫），一种血小板源性生长因子受体的蛋白酪氨酸激酶抑制剂，结合皮下注射。注射IFN-α不仅能有效降低肿瘤重量（减少81.8%）和微血管密度（减少70.2%），而且还能抑制肺转移（减少100%）。此外，对人肝细胞癌组织中血小板源性生长因子受体a的免疫组织化学分析揭示了其与术后复发的相关性，尤其是在无微血管侵犯的患者中。结论：不同转移潜能肿瘤之间的肝细胞癌血管内皮基因表达存在差异。血小板源性生长因子受体α在高转移性肝细胞癌的内皮细胞中过度表达，可能作为预测转移的生物标志物和高转移性肝细胞癌的治疗靶点。
Purpose: Little information is available on the heterogeneity of the vascular endothelium in hepatocellular carcinoma. The aim of this study was to identify the differentially expressed genes in tumor endothelial cells from highly metastatic hepatocellular carcinoma.Experimental Design: Magnetic beads conjugated with anti-CD31 antibody were used to isolate vascular endothelial cells from hepatocellular carcinoma xenografts with different metastatic potentials in nude mice. Gene expression profiles for different endothelial cells were compared by use of cDNA microarray. The up-regulated gene was confirmed by reverse transcription- PCR, real-time PCR, and immunchistochemistry.Results: cDNA microarray analysis revealed differential expression patterns in seven genes consistently presented in endothelial cells isolated from hepatocellular carcinoma with different metastatic potentials. Overexpression of platelet- derived growth factor receptor a was found only in the endothelium of highly metastatic hepatocellular carcinoma, which was confirmed by reverse transcription- PCR, real-time PCR, and immunohistochemistry. Oral administration of ST1571 (imatinib mesylate or Glivec), a protein tyrosine kinase inhibitor of platelet-derived growth factor receptor, combined with s.c. injection of IFN-alpha not only effectively reduced tumor weight (by 81.8%) and microvessel density (by 70.2%) but also inhibited lung metastasis (by 100%). Furthermore, immunohistochemical analysis of platelet-derived growth factor receptor a in human hepatocellular carcinoma tissues revealed its correlation with postoperative recurrence, especially in patients without microvessel invasion.Conclusions: The gene expression of hepatocellular carcinoma vascular endothelium is different between tumors with different metastatic potential. Platelet-derived growth factor receptor alpha, which is overexpressed in endothelium of highly metastatic hepatocellular carcinoma, may serve as a biomarker for predicting metastasis and a therapeutic target for highly metastatic hepatocellular carcinoma.