Table 2.
The roles of major adhesion molecules and other factors in VM
| Formation mechanisms | Functions in VM formation | References |
|---|---|---|
| MMPs, Ln-5 γ2 chain | The activation of MMPs motivates the cleavage of Ln-5γ2 chain into pro-migratory γ2 and γ2x fragments which participate in the plasticity of matrix, migration, invasion and formation of VM | 28,33,49 |
| PI3K/Akt | PI3K/Akt signal pathway participates in VM formation by regulating the activity of MT1-MMP, MMP-2 and the cleavage of Ln-5γ2 chain | 35 |
| VE-cadherin, EphA2 | VM-cadherin mediates the activities of EphA2, and the phosphorylation of it could activate PIK-3 which promotes VM formation by MMPs and Ln-5 γ2 chain | 28,29,31,50 |
| FAK | FAK activates ERK1/2 which mediates MMPs, thus participating in the plasticity of matrix, migration, invasion and VM formation | 38,39 |
| TFPI1/2 | TFPI-1 is associated with perfusion of VM by its anticoagulant function; TFPI2 through the interaction with MMP-2 was involved in endothelial-cell matrix remodelling and VM formation | 58 |
| VEGF, VEGFR1/2 | VEGF-A upregulates VE-cadherin, EphA2 and MMPs expressions; VEGFR2 expression contributes to the formation of capillary-like structures (VM) | 59–64 |
| Hypoxia, HIF-1α | Hypoxia promotes VM formation by inducing EMT; HIF-1α activates expression of VEGF, and the latter is related to VM formation | 20,36,66,67 |
| Gal-3 | Gal-3 mediates the expression of VE-cadherin and MMP-2 which have been confirmed to promote VM formation. Silencing of Gal-3 leads to the inhibition of VE-cadherin and IL-8 promoter activities | 74 |
| cAMP | The increase of cAMP results in inhibition of VM formation through activation of Epac/Rapl pathway and inhibition of MMP-2 and MT1-MMP expression | |
| Nodal | Activation of Nodal contributes to VM formation by increasing VE-cad expression. And inhibition of VM formation could be inhibited via the activation of Nodal signal mediated by cAMP | 77 |
| COX2 | COX-2 results in up-regulation of VEGF expression by activating PKC, and PGE-2 expression, thereby promoting VM formation | 28,79 |
| CSC, EMT | CSC and EMT are associated with VM formation. And CSC may be implicated in VM formation by EMT induction | 113,118,119,125,126,128–132 |
VM, vasculogenic mimicry; MMPs, matrix metalloproteinase; Ln-5 γ2, laminin 5 (Ln-5) γ2 chain; PI3K, phosphoinositide 3-kinase; EphA2, epithelial cell kinase; FAK, focal adhesion kinase; TFPI1/2, tissue factor pathway 1/2; VEGF, vascular endothelial growth factor; VEGFR1/2, vascular endothelial growth factor receptor 1/2; HIF-1α, hypoxiainducible factor1-α; Gal-3, galectin-3; cAMP, cyclic adenosine monophosphate; COX2, Cyclooxygenase; CSC, cancer stem cell; EMT, epithelial-mesenchymal transition.