Regulatory mechanisms and therapeutic targeting of vasculogenic mimicry in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a typical hyper-vascular solid tumor; aberrantly rich in tumor vascular network contributes to its malignancy. Conventional anti-angiogenic therapies seem promising but transitory and incomplete efficacy on HCC. Vasculogenic mimicry (VM) is one of functional microcirculation patterns independent of endothelial vessels which describes the plasticity of highly aggressive tumor cells to form vasculogenic-like networks providing sufficient blood supply for tumor growth and metastasis. As a pivotal alternative mechanism for tumor vascularization when tumor cells undergo lack of oxygen and nutrients, VM has an association with the malignant phenotype and poor clinical outcome for HCC, and may challenge the classic anti-angiogenic treatment of HCC. Current studies have contributed numerous findings illustrating the underlying molecular mechanisms and signaling pathways supporting VM in HCC. In this review, we summarize the correlation between epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and VM, the role of hypoxia and extracellular matrix remodeling in VM, the involvement of adjacent non-cancerous cells, cytokines and growth factors in VM, as well as the regulatory influence of non-coding RNAs on VM in HCC. Moreover, we discuss the clinical significance of VM in practice and the potential therapeutic strategies targeting VM for HCC. A better understanding of the mechanism underlying VM formation in HCC may optimize anti-angiogenic treatment modalities for HCC.