Zhang Danfang, Sun Baocun, Zhao Xiulan, Ma Yuemei, Ji Ru, Gu Qiang, Dong Xueyi, Li Jing, Liu Fang, Jia Xiaohua, Leng Xue, Zhang Chong, Sun Ran, Chi Jiadong
Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
Mol Cancer. 2014 Sep 8;13:207. doi: 10.1186/1476-4598-13-207.
Hypoxia induced by antiangiogenic agents is linked to the generation of cancer stem cells (CSCs) and treatment failure through unknown mechanisms. The generation of endothelial cell-independent microcirculation in malignant tumors is defined as tumor cell vasculogenic mimicry (VM). In the present study, we analyzed the effects of an antiangiogenic agent on VM in triple-negative breast cancer (TNBC).
Microcirculation patterns were detected in patients with TNBC and non-TNBC. Tientsin Albino 2 (TA2) mice engrafted with mouse TNBC cells and nude mice engrafted with human breast cancer cell lines with TNBC or non-TNBC phenotypes were administered sunitinib and analyzed to determine tumor progression, survival, microcirculation, and oxygen concentration. Further, we evaluated the effects of hypoxia induced with CoCl2 and the expression levels of the transcription factor Twist1, in the presence or absence of a Twist siRNA, on the population of CD133(+) cells and VM in TNBC and non-TNBC cells.
VM was detected in 35.8 and 17.8% of patients with TNBC or with non-TNBC, respectively. The growth of tumors in TNBC and non-TNBC-bearing mice was inhibited by sunitinib. The tumors in TA2 mice engrafted with mouse TNBCs and in mice engrafted a human TNBC cell line (MDA-MB-231) regrew after terminating sunitinib administration. However, this effect was not observed in mice engrafted with a non-TNBC tumor cell line. Tumor metastases in sunitinib-treated TA2 mice was accelerated, and the survival of these mice decreased when sunitinib was withdrawn. VM was the major component of the microcirculation in sunitinib-treated mice with TNBC tumors, and the population of CD133+ cells increased in hypoxic areas. Hypoxia also induced MDA-MB-231 cells to express Twist1, and CD133(+) cells present in the MDA-MB-231 cell population induced VM after reoxygenation. Moreover, hypoxia did not induce MDA-MB-231 cells transfected with an sh-Twist1 siRNA cell to form VM and generate CD133(+) cells. Conversely, hypoxia induced MCF-7 cells transfected with Twist to form VM and generate CD133+ cells.
Sunitinib induced hypoxia in TNBCs, and Twist1 expression induced by hypoxia accelerated VM by increasing population of CD133(+) cells. VM was responsible for the regrowth of TNBCs sunitinib administration was terminated.
抗血管生成药物诱导的缺氧与癌症干细胞（CSCs）的产生以及治疗失败通过未知机制相关联。恶性肿瘤中不依赖内皮细胞的微循环生成被定义为肿瘤细胞血管生成拟态（VM）。在本研究中，我们分析了一种抗血管生成药物对三阴性乳腺癌（TNBC）中VM的影响。
在TNBC和非TNBC患者中检测微循环模式。给接种小鼠TNBC细胞的津白2（TA2）小鼠以及接种具有TNBC或非TNBC表型的人乳腺癌细胞系的裸鼠施用舒尼替尼，并进行分析以确定肿瘤进展、生存、微循环和氧浓度。此外，我们评估了在有或没有Twist siRNA的情况下，用CoCl₂诱导的缺氧以及转录因子Twist1的表达水平对TNBC和非TNBC细胞中CD133(+)细胞群体和VM的影响。
分别在35.8%的TNBC患者和17.8%的非TNBC患者中检测到VM。舒尼替尼抑制了携带TNBC和非TNBC小鼠的肿瘤生长。在接种小鼠TNBC的TA2小鼠以及接种人TNBC细胞系（MDA-MB-231）的小鼠中，停止施用舒尼替尼后肿瘤重新生长。然而，在接种非TNBC肿瘤细胞系的小鼠中未观察到这种效应。在舒尼替尼治疗的TA2小鼠中肿瘤转移加速，并且停止施用舒尼替尼时这些小鼠的生存时间缩短。VM是舒尼替尼治疗的TNBC肿瘤小鼠微循环的主要组成部分，并且缺氧区域中CD133+细胞群体增加。缺氧还诱导MDA-MB-231细胞表达Twist1，并且MDA-MB-231细胞群体中存在的CD133(+)细胞在复氧后诱导VM形成。此外，缺氧未诱导用sh-Twist1 siRNA转染的MDA-MB-231细胞形成VM并产生CD133(+)细胞。相反，缺氧诱导用Twist转染的MCF-7细胞形成VM并产生CD133+细胞。
舒尼替尼在TNBC中诱导缺氧，缺氧诱导的Twist1表达通过增加CD133(+)细胞群体加速VM形成。VM是停止施用舒尼替尼后TNBC重新生长的原因。
