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

Abstract

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metastases in sunitinib-treated TA2 mice was accelerated, and the survival of these mice decreased when sunitinib was withdrawn.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.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-207) contains supplementary material, which is available to authorized users.

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

“…15,24 Moreover, targeting VEGF, VEGF receptors or endothelial cells shows limited effectiveness on VM formed by tumor cells. 25 Previously, we found there is increased VM in TNBC compared within non-TNBC. Based on previous studies, we hypothesize that the VM channels in TNBC are responsible for the tumor rebound and treatment failure of anti-angiogenic agents.…”

The relationship between vasculogenic mimicry and epithelial‐mesenchymal transitions

“…Twist is capable to open nuclear membrane pores with the help of an accessory protein and enters the nucleus to regulate transcription of downstream genes that are involved in the process of VM [38]. However, Twist2 share several of similar functions including their regulation of haematological malignancies and their role in cancer progression and metastasis with Twist1 [39][40][41]. Studies found that Twist1 and Twist2 were both up-regulated in metastasis-associated colon cancer.…”

Aberrant Expression of Markers of Cancer Stem Cells in Gastric Adenocarcinoma and their Relationship to Vasculogenic Mimicry

“…VM is associated with increased tumor aggressive biology and tumorrelated patient mortality. The channel of VM consists of plasticity of tumor cells in the external wall, remodeling of the extracellular matrix (ECM) on the inner wall, and connection to the host microcirculation system (Sun et al, 2011;Yao et al, 2013;Zhang et al, 2014) with genetically dysregulated tumor cells having a pluripotent embryoniclike gene type (Hendrix et al, 2003), suggesting the participation of CSCs. We and others have demonstrated that vascular niche may regulate CSCs fate (Hilbe et al, 2004;EI Hallani et al, 2010; and promote metastasis through the down-regulation of E-cadherin.…”