Cancer stem-like cells directly participate in vasculogenic mimicry channels in triple-negative breast cancer

Abstract

Objective Vasculogenic mimicry (VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors. However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells (CSCs) are positively correlated with VM. In this study, triple-negative breast cancer (TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs. Methods The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples. The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs. Results CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro . MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo . Conclusions CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.

An Overview of Vasculogenic Mimicry in Breast Cancer

“…Disease free survival and overall survival p = 0.015 134 (30.6%) VM presence was higher in TNBC vs. non TNBC p = 0.004 (29) 100 (29%) VM presence was higher in TNBC vs. non TNBC p = 0.020 (30) VM correlated with poorer overall survival p = 0.015 174 (24.7%) VM presence was higher in TNBC vs. non TNBC p = 0.044 (31) 120 (22.5%) VM correlated with positive node status; p = 0.027 (32) a higher tumor stage p = 0.022 and higher levels of HER2 p = 0.018 VM did not correlate with ERalpha or PR status p = 0.143 (39). Besides, in a study that analyzed 200 breast cancer patient samples, an association of the presence of Osteopontin and VM was observed (27).…”

“…However, not all reports agree on the specific presence of CSC markers and the presence of VM. For example, Sun et al found an association between VM formation and the presence of ALDH1 and CD44+CD24phenotype, but not with the presence of CD133 (30). Therefore, it will be important to determine whether there is a single type of CSC in breast cancer or whether populations with stem cell characteristics are variable among tumors.…”

“…There is a higher proportion of triple-negative tumors with VM compared to tumors positive for ER, PR, and/or HER2. Accordingly, these tumors also have a greater number of vessels formed by VM (28)(29)(30)(31). However, this association is controverted (26,32).…”

Comparison of Hydrogels for the Development of Well-Defined 3D Cancer Models of Breast Cancer and Melanoma

“…MCF-7's colonies were smaller and the cells proliferated less. Other groups reported a higher invasion of MDA-MB-231 in Matrigel, compared to MCF-7 [33]. Mel Im and MV3 also have been shown to have invasive properties through Matrigel [34,35].…”

Cancer Stem Cells and Neovascularization

“…The breast tumor cells lining VM channels on Matrigel were also found to express CD133. Via using a three-dimensional reconstructed image to show the spatial relationship between CSCs and VM, Sun et al has provided direct evidence indicating that tumor cells lining VM channels were derived from CSCs [ 35 ].…”