title: Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization.
abstract: 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.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Fu
authors.forename: Hua-Xiang
authors.initials: HX
authors.lastname: Xu
authors.forename: Zong-Tao
authors.initials: ZT
authors.lastname: Chai
authors.forename: Qiang-Bo
authors.initials: QB
authors.lastname: Zhang
authors.forename: Ling-Qun
authors.initials: LQ
authors.lastname: Kong
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhu
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Zheng-Gang
authors.initials: ZG
authors.lastname: Ren
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; C021751:tanshinone