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

Abstract

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-1a, 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.

An Overview of Vasculogenic Mimicry in Breast Cancer

“…Overexpression of factors regulating VM in breast tumors, such as HIF1alpha, VE-cadherin, and EPHA2 has also been reported (33)(34)(35)(36). In a mouse breast cancer model, inhibition of angiogenesis promoted VM by expression of VE-Cadherin and other VM regulators in triple-negative tumors (37). In the MDA-MB-231 cell line (derived from a triple-negative tumor) which can form a pattern of tubular structures in matrigel, low expression of miR-204 was observed, while overexpression of miR-204 decreased the VM.…”

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

“…Bevacizumab (trade name Avastin) slightly contributed to progression-free survival (PFS) but not overall survival (OS) in glioma patients 3 . Several preclinical studies speculate that vasculogenic mimicry (VM) contributes to anti-angiogenesis therapeutic resistance [4][5][6] .…”

RPV‐modified epirubicin and dioscin co‐delivery liposomes suppress non‐small cell lung cancer growth by limiting nutrition supply

“…Among them, VEGFA plays a key role in the process of angiogenesis . Recent studies have shown that a variety of cancer cells can upregulate the expression of VEGFA, thereby promoting tumor‐induced angiogenesis . With this in mind, we used the CAM assay to test the anti‐angiogenic effect of liposomal formulations.…”