Abstract
Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.
Highlights
Solid malignant tumors possessing the characteristics, such as rapid growth and metastasis, a high tumor grade, and bidirectional differentiation or uncommitted differentiation status, could build tubular structures lined by aggressive tumor cells and mimic regular blood vessels to meet their requirement for masses of oxygen and nutrients [1,2,3,4]
The inhibitory effect of brucine on MDA-MB-231 cells was firstly observed under microscope
We provide the first evidence illustrating the role of brucine in the modulation of vasculogenic mimicry (VM) formation in the triple-negative breast cancer (TNBC) cell line MDA-MB-231
Summary
Solid malignant tumors possessing the characteristics, such as rapid growth and metastasis, a high tumor grade, and bidirectional differentiation or uncommitted differentiation status, could build tubular structures lined by aggressive tumor cells and mimic regular blood vessels to meet their requirement for masses of oxygen and nutrients [1,2,3,4]. The tumors creating this endothelial independent vascularization with the CD34 negative and periodic acid Schiff (PAS) positive patterns are defined to have vasculogenic mimicry (VM) [2, 3].
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