Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy

Figure 1 Hypothetical model for the molecular signaling pathways of vasculogenic mimicry in tumors and anti-vasculogenic mimicry (VM) therapy strategies. (1) The down-regulation of BMP-4 activity can lead to reduce expression of EphA2 and VE-cad; (2) TEL regulate VM by synergizing with signaling pathways downstream of RAS; (3) Celecoxib, COX-2 inhibition, may inhibit vascular channel formation, which is abrogated by addition of PGE2; (4) cAMP inhibits VM by activating Epac/Rap1 which produces Rap1-GTP; (5) Activation of Nodal signaling supports VM and expression of the VE-cad. Inhibition of the Nodal signaling pathway results in a reduction in keratin and VE-cad; (6) Knockdown of Id2 expression can inhibit VE-cad expression and abrogate the formation of tubular networks; (7) Gal-3 silencing can result decrease of VE-cadherin activities due to enhanced recruitment of EGR-1; (8) The decreasing in Gal-1 expression can provoke a marked decrease in BEX2, which impairs vasculogenic mimicry channel formation; (9) Over-expression of Mig-7 increased γ2 chain domain III fragments. Laminin 5 is the only laminin that contains the γ² chain, which following cleavage into promigratory fragments, the domain III region, causes increased levels of MMP-2, and MT1-MMP cooperate to cleave γ² chain into fragments that promote tumor cell VM; (10) Hypoxia→VEGF→EphA2→MMPs→VM; (11) VE-cadherin can promote the interaction between FAK and EphA2, phosphorylated EphA2 can form an interaction with FAK, which would lead to phosphorylation and activation of FAK. The signal transduction pathways activated through VE-cad and EphA2 can converge, resulting in activation of PI3K; (12) PI3K regulates MT1-MMP activity, which promotes the conversion of pro-MMP into its active conformation through an interaction with TIMP-2. Both enzymatically active MT1-MMP and MMP-2 may then promote the cleavage of the laminin 5(Ln-5) γ² chain in pro-migratory γ^2, and γ^2x fragments, the deposition of these fragments into tumor extracellular milieu may result in VM formation; (13) Blockade of TFPI-2 is able to suppress MMP-2 activation and prevent VM formation. Moreover, TFPI-1 has anticoagulant function of relevance for perfusion of VM; (14) Several drugs express specific anti-VM effects. Genistein inhibits VE-cad expression; COL-3 inhibits VE-cad, MMP-2 and MT1-MMP expression respectively. Doxycycline inhibits MMP-2 expression. Thalidomide inhibits MMP-2 and VEGF expression. In addition, forskolin inhibits VM formation through MAPK and PI3K pathway. VM: Vasculogenic mimicry; COX: Cyclooxygenase; VE-cad: Vascular endothelial-cadherin; MMPs: Matrix metalloproteinase; EphA2: Epithelial cell kinase; FAK: Focal adhesion kinase; VEGF: Endothelial growth factor.