Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

Journal of Hematology & Oncology

Zhao-You Tang¹  Zheng-Gang Ren¹  Lu Lu¹  Xiao-Dong Zhu¹  Ling-Qun Kong¹  Qiang-Bo Zhang¹  Zong-Tao Chai¹  Hua-Xiang Xu³  Yan-Ling Fu²  Hui-Chuan Sun¹  Liang Liu³  Wen-Quan Wang³ 

[1] Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis & Cancer Invasion (Fudan University), the Chinese Ministry of Education, 136 Yi Xue Yuan Road, Shanghai 200032, China;Department of Neurology, Tongji Hospital, Tongji University, 390 Xin Cun Road, Shanghai 200032, China;Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai 200032, China

关键词: Metastasis;    Hepatocellular carcinoma;    Palliative resection;    Vascular normalization;    Tanshinone IIA;   

Others  :  821891
DOI  :  10.1186/1756-8722-5-69

 received in 2012-10-08, accepted in 2012-10-16,  发布年份 2012

【 摘 要 】

Background

Promotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR) of hepatocellular carcinoma (HCC).

Methods

A liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential) and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs) treated with tanshinone IIA.

Results

PR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT) in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α) or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR) upregulation. Although the microvessel density (MVD) of residual tumor tissue increased after PR, the microvessel integrity (MVI) was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization.

Conclusions

Our results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical benefit of preventing postsurgical recurrence.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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