Twist1 expression induced by sunitinib accelerates tumor cell vasculogenic mimicry by increasing the population of CD133+ cells in triple-negative breast cancer

Molecular Cancer

Research

Xiaohua Jia¹  Ran Sun¹  Jiadong Chi¹  Chong Zhang¹  Fang Liu¹  Ru Ji¹  Yuemei Ma¹  Xueyi Dong¹  Xue Leng²  Jing Li³  Danfang Zhang³  Xiulan Zhao³  Qiang Gu³  Baocun Sun⁴ 

[1] Department of Pathology, Tianjin Medical University, 300070, Tianjin, China;Department of Pathology, Tianjin Medical University, 300070, Tianjin, China;Department of Pathology, Cancer Hospital of Tianjin Medical University, 300060, Tianjin, China;Department of Pathology, Tianjin Medical University, 300070, Tianjin, China;Department of Pathology, General Hospital of Tianjin Medical University, 300070, Tianjin, China;Department of Pathology, Tianjin Medical University, 300070, Tianjin, China;Department of Pathology, General Hospital of Tianjin Medical University, 300070, Tianjin, China;Department of Pathology, Cancer Hospital of Tianjin Medical University, 300060, Tianjin, China;Department of Pathology, Tianjin Medical University and General Hospital and Cancer Hospital, 300070, Tianjin, PR, China;

关键词: Triple-negative breast cancer;    Cancer stem cell;    Vasculogenic mimicry;    Angiogenesis;    Sunitinib;    Twist1;   

DOI  :  10.1186/1476-4598-13-207

 received in 2014-04-16, accepted in 2014-08-29,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundHypoxia 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).MethodsMicrocirculation 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.ResultsVM 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.ConclusionsSunitinib 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.

【 授权许可】

Unknown   
© Zhang et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.