Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization.
Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization.
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丹参酮 IIA 抑制肝细胞癌姑息性切除术后的转移，并部分通过血管正常化延长生存期
DOI：
10.1186/1756-8722-5-69
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发表时间：
2012-11-08
影响因子：
28.5
通讯作者：
Tang ZY
中科院分区：
文献类型：
--
作者：
Wang WQ;Liu L;Sun HC;Fu YL;Xu HX;Chai ZT;Zhang QB;Kong LQ;Zhu XD;Lu L;Ren ZG;Tang ZY
背景促进血管内皮细胞正常化可以恢复肿瘤的氧合，并阻止肿瘤细胞的侵袭、血管内和转移。因此，我们研究了血管活性药物丹参酮IIA能否通过诱导肝细胞癌姑息性切除(PR)后的血管正常化来抑制肿瘤转移。在PR切除1个肿瘤后，评价丹参酮IIA对转移、肿瘤血管形成和生存的影响。丹参酮IIA处理的小鼠肿瘤来源的内皮细胞(TECs)形成管状结构。结果PR可显著促进残留肝癌转移。丹参酮IIA不能抑制单种移植瘤的生长，但能减少转移的发生。此外，它还抑制PR促进的转移，更重要的是，延长宿主存活时间。丹参酮IIA在体内可减轻残留肿瘤缺氧，抑制上皮-间充质转化，但在体外缺氧条件下不下调肿瘤细胞缺氧诱导因子-1α(HIF-1α)或逆转上皮-间充质转化。丹参酮IIA直接促进血管内皮细胞的管形成，与血管内皮细胞生长因子受体1/血小板衍生生长因子受体(VEGFR1/PDGFR)上调有关。虽然PR后残留肿瘤组织的微血管密度(MVD)增加，但微血管完整性(MVI)仍较低。丹参酮IIA不抑制MVD，但显著增加MVI，导致血管正常化。结论丹参酮IIA可抑制PR相关的肝癌转移。抑制的结果是促进VEGFR1/PDGFR相关的血管正常化。这一应用证明了预防术后复发的潜在临床益处。
BackgroundPromotion 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).MethodsA 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.ResultsPR 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.ConclusionsOur 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.
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影响因子：
50.3
作者：
Rolny, Charlotte;Mazzone, Massimiliano;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
3.4
作者：
Jia, Jin-Bin;Wang, Wen-Quan;Tang, Zhao-You
通讯作者：
Tang, Zhao-You
影响因子：
33.6
作者：
Goel S;Duda DG;Xu L;Munn LL;Boucher Y;Fukumura D;Jain RK
通讯作者：
Jain RK
影响因子：
4.8
作者：
Erber, Ralf;Thurnher, Andreas;Vajkoczy, Peter
通讯作者：
Vajkoczy, Peter
瘤周肝组织中巨噬细胞集落刺激因子1受体的高表达与肝细胞癌根治性切除后的不良预后相关
影响因子：
5.8
作者：
Jia, Jin-Bin;Wang, Wen-Quan;Tang, Zhao-You
通讯作者：
Tang, Zhao-You