Sun Huizhi, Zhang Danfang, Yao Zhi, Lin Xian, Liu Jiameng, Gu Qiang, Dong Xueyi, Liu Fang, Wang Yi, Yao Nan, Cheng Siqi, Li Linqi, Sun Shuya
a Department of Pathology , Tianjin Medical University , Tianjin , China.
b Department of Pathology , General Hospital of Tianjin Medical University , Tianjin , China.
Cancer Biol Ther. 2017 Apr 3;18(4):205-213. doi: 10.1080/15384047.2017.1294288. Epub 2017 Feb 21.
Agents that target angiogenesis have shown limited efficacy for human triple-negative breast cancer (TNBC) in clinical trials. Along with endothelium-dependent vessels, there is also vasculogenic mimicry (VM) in the microcirculation of malignant tumors. The role of VM is not completely understood regarding anti-angiogenic treatment. In this study, human TNBC MDA-MB-231 and Hs578T and non-TNBC MCF-7 and BT474 tumor-bearing mice were treated with sunitinib, an anti-angiogenic drug, using a clinically relevant schedule. The drug was administered for one week and then discontinued. Tumor growth and invasion were observed, and the microcirculation patterns were detected with PAS/endomucin staining. Moreover, hypoxia and VM-associated proteins were evaluated with Hypoxyprobe kits and immunohistochemistry, respectively. Sunitinib significantly inhibited tumor growth in the TNBC and non-TNBC tumors. However, MDA-MB-231 and Hs578T tumors regrew and were more aggressive when the treatment was stopped. The discontinuation had no significant effect on the behavior of the non-TNBC MCF-7 and BT474 tumors. The growth of endothelium-dependent vessels in the TNBC MDA-MB-231 and Hs578T tumors were blocked by sunitinib, during which the number of VM channels significantly increased and resulted in a rebound of endothelium-dependent vessels after sunitinib discontinuation. Moreover, the VM-associated proteins VE-cadherin and Twist1 upregulated in the sunitinib-treated MDA-MB-231 and Hs578T tumors. Furthermore, the clinical significance of this upregulation was validated in 174 human breast cancers. The results from human breast cancer specimens indicated that there were more VM-positive TNBC cases than those in non-TNBC cases. HIF-1α, MMP2, VE-cadherin, and Twist1 were also expressed in a higher level in human TNBC compared with non-TNBC. In aconclusion, sunitinib promoted TNBC invasion by VM. The VM status could be helpful to predict the efficacy of anti-angiogenic therapy in patients with TNBC.
在临床试验中，靶向血管生成的药物对人类三阴性乳腺癌（TNBC）的疗效有限。除了内皮依赖性血管外，恶性肿瘤的微循环中还存在血管生成拟态（VM）。关于抗血管生成治疗，VM的作用尚未完全明确。在本研究中，采用与临床相关的给药方案，用抗血管生成药物舒尼替尼治疗携带人TNBC MDA-MB-231和Hs578T以及非TNBC MCF-7和BT474肿瘤的小鼠。药物给药一周后停药。观察肿瘤生长和侵袭情况，并用PAS/内黏液素染色检测微循环模式。此外，分别用Hypoxyprobe试剂盒和免疫组织化学评估缺氧和VM相关蛋白。舒尼替尼显著抑制TNBC和非TNBC肿瘤的生长。然而，当治疗停止时，MDA-MB-231和Hs578T肿瘤复发且更具侵袭性。停药对非TNBC MCF-7和BT474肿瘤的行为没有显著影响。舒尼替尼阻断了TNBC MDA-MB-231和Hs578T肿瘤中内皮依赖性血管的生长，在此期间VM通道数量显著增加，并导致舒尼替尼停药后内皮依赖性血管反弹。此外，VM相关蛋白VE-钙黏蛋白和Twist1在舒尼替尼治疗的MDA-MB-231和Hs578T肿瘤中上调。此外，在174例人类乳腺癌中验证了这种上调的临床意义。人类乳腺癌标本的结果表明，VM阳性的TNBC病例比非TNBC病例更多。与非TNBC相比，HIF-1α、MMP2、VE-钙黏蛋白和Twist1在人类TNBC中的表达水平也更高。总之，舒尼替尼通过VM促进TNBC侵袭。VM状态可能有助于预测TNBC患者抗血管生成治疗的疗效。
