Epithelial-to-endothelial transition and cancer stem cells: two cornerstones of vasculogenic mimicry in malignant tumors

Baocun Sun _, Danfang Zhang, Nan Zhao and Xiulan Zhao

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Oncotarget. 2017; 8:30502-30510. https://doi.org/10.18632/oncotarget.8461

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Baocun Sun1,2,3,*, Danfang Zhang1,2,* Nan Zhao1,2 and Xiulan Zhao1,2

1 Department of Pathology, Tianjin Medical University, Tianjin, China

2 Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China

3 Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, China

* These authors have contributed equally to this work

Correspondence to:

Baocun Sun, email:

Keywords: vasculogenic mimicry, epithelial-to-endothelial transition, cancer stem cells, hypoxia, LPPCN

Received: November 09, 2015 Accepted: February 14, 2016 Published: March 29, 2016


Vasculogenic mimicry (VM) is a functional microcirculation pattern in malignant tumors accompanied by endothelium-dependent vessels and mosaic vessels. VM has been identified in more than 15 solid tumor types and is associated with poor differentiation, late clinical stage and poor prognosis. Classic anti-angiogenic agents do not target endothelium-dependent vessels and are not efficacious against tumors exhibiting VM. Further insight into the molecular signaling that triggers and promotes VM formation could improve anti-angiogenic therapeutics. Recent studies have shown that cancer stem cells (CSCs) and epithelium-to-endothelium transition (EET), a subtype of epithelial-to-mesenchymal transition (EMT), accelerate VM formation by stimulating tumor cell plasticity, remodeling the extracellular matrix (ECM) and connecting VM channels with host blood vessels. VM channel-lining cells originate from CSCs due to expression of EMT inducers such as Twist1, which promote EET and ECM remodeling. Hypoxia and high interstitial fluid pressure in the tumor microenvironment induce a specific type of cell death, linearly patterned programmed cell necrosis (LPPCN), which spatially guides VM and endothelium-dependent vessel networks. This review focuses on the roles of CSCs and EET in VM, and on possible novel anti-angiogenic strategies against alternative tumor vascularization.

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