| Yunyan Luan,Hongwei Xue,Lijian Zhang,Ruyong Yao,Hongsheng Yu. Effect of grape seed proanthocyanidins on tumor vasculogenic mimicry in liver cancer xenograft model. Oncol Transl Med, 2014, 13: 572-577. |
| 葡萄原花青素对H22肝癌移植瘤血管生成拟态的作用及其机制研究 |
| Effect of grape seed proanthocyanidins on tumor vasculogenic mimicry in liver cancer xenograft model |
| Received:October 28, 2014 Revised:December 04, 2014 |
| DOI：10.1007/s10330-314-0019-3 |
| 中文关键词: 血管生成拟态，葡萄原花青素，H22移植瘤，VEGF, EphA2 ，MMP-2 |
| 英文关键词: vasculogenic mimicry; H22 hepatoma carcinoma model; grape seed proanthocyanidins; VEGF, EphA2, MMP-2 |
| 基金项目: |
| Author Name | Affiliation | E-mail | | Yunyan Luan | The Affiliated Hospital of Qingdao University | xiaoluanhai@sina.com | | Hongwei Xue | The Affiliated Hospital of Qingdao University | | | Lijian Zhang | The Affiliated Hospital of Qingdao University | | | Ruyong Yao | The Affiliated Hospital of Qingdao University | | | Hongsheng Yu* | The Affiliated Hospital of Qingdao University | qdhsyu@126.com |
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| 中文摘要: |
| 摘要 目的：探讨葡萄原花青素（ grape seed proanthocyanidins，GSPs）对小鼠H22肝癌移植瘤血管生成拟态（vasculogenic mimicry, VM）形成的抑制作用及可能的机制。方法：75只昆明小鼠，皮下接种H22肝癌细胞悬液建立荷瘤模型，随机分为荷瘤对照组，恩度组(4mg/㎏)，葡萄原花青素低(50mg/㎏)、中(100mg/㎏)、高剂量组(200mg/㎏)，每组15只，连续干预10天，称量瘤重，计算抑瘤率。运用CD34和过碘酸雪夫（PAS）双重染色法检测肿瘤组织中VM的形成及密度；免疫组织化学法检测VEGF, EphA2 和MMP-2的蛋白表达水平。结果：各个干预组的抑瘤率分别是6.87％,17.81％,27.43％,53.52％，与荷瘤对照组相比，GSPs低剂量组和高剂量组的H22移植瘤的生长明显受到抑制（P＜0.01）。CD34-PAS双重染色法检测显示，低剂量的GSPs组(100mg/㎏) 和高剂量的GSPs组(200mg/㎏)的VM密度明显低于荷瘤对照组（P＜0.01）。免疫组化结果显示，VEGF, EphA2 and MMP-2蛋白的表达水平明显降低（P＜0.001）。结论：葡萄原花青素可以抑制H22肝癌移植瘤VM的形成，其机制可能与下调VEGF, EphA2 和 MMP-2的表达有关。 |
| 英文摘要: |
| Objective: As a novel blood supply pattern, vasculogenic mimicry (VM) has attracted increasingly attention in recent years, which may partly compensate for the absence of feeding and facilitate tumor perfusion. However, anti-angiogenic drugs have little effect on VM. The grape seed proanthocyanidins (GSPs), a kind of promising bioactive phytochemical, has shown anti-carcinogenesis and anti-angiogenic in several tumor models. However, GSPs regulation of VM and its possible mechanisms in a H22 hepatoma carcinoma model remain not clear. The aim of this study was to examine the effects of GSPs on proliferation and VM in a H22 hepatoma carcinoma model and to investigate the underlying mechanism. Methods: Seventy-five mice were divided into the control group and experimental groups treated with different concentration of GSPs. CD34-PAS dual staining was employed to identify the VM structure. The immunohistochemical staining for investigating the expression of VEGF, EphA2 and MMP-2 protein was performed. Results: Treatment of the H22 model with Endostar (4 mg/kg), 50, 100, 200 mg/kg of the GSPs resulted in 6.87%, 17.81%, 27.43%, 53.52% inhibition in tumor growth, respectively.
The mean weight of tumors were significantly lower in GSPs (100 mg/kg) and GSPs (200 mg/kg) groups than in the control group (all P < 0.01). Similarly, compared with the control group, the number of VM channels were significantly reduced in GSPs (100 mg/kg) and GSPs (200 mg/kg) groups (all P < 0.01). Immunohistochemistry showed significant decreases in the expression levels of VEGF, EphA2 and MMP-2 protein in GSPs (100 mg/kg) and GSPs (200 mg/kg) groups when compared with control group (all P < 0.001). Conclusion: This is the first report providing evidence that GSPs inhibit the VM structure by regulation of the VEGF/EphA2/MMPs signaling pathway. Therefore, we concluded that GSPs has the potential of being a clinical anti-VM inhibitor. |
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