Vasculogenic minicry (VM), an alternative blood supply modality except to endothelial cells-mediated vascular network, is a potential therapeutic target for ovarian cancer due to VM correlated with poor prognosis in ovarian cancer patients. Accelerated extracellular matrix (ECM) degradation is prerequisite for VM formation induced by epithelial-mesenchymal transition (EMT). Previous reports demonstrate uPA has ability to degrade ECM thereby promoting tumor angiogenesis. Also, exogenous cRGD sequence enables to modulate uPA expression, attenuate EMT and suppress endothelial-lined channels. Till now, the correlation of uPA and VM formation and the effect of exogenous cRGD on VM formation remain unknown. Herein, we validate uPA expression is positively correlated with VM formation in ovarian cancer tissues (90 cases) and ovarian cancer cells (SKOV-3, OVCAR-3 and A2780 cells). In particular, silencing uPA experiments show that down-regulated uPA causes notable decrease for the complete channels formed by SKOV-3 and OVCAR-3 cells. Mechanism study discloses uPA promotes VM formation by regulating AKT/mTOR/MMP-2/Laminin5γ2 signal pathway. The result demonstrates uPA may serve as therapeutic target of VM for ovarian cancer. Also, it is found exogenous cRGD enables to inhibit VM formation in ovarian cancer via not only down-regulating uPA expression but also reducing EMT. Exogenous cRGD may be a promising angiogenic inhibitor for ovarian cancer therapy due to its inhibiting effect on VM formation as well as endothelial cells-mediated vascular network.
Keywords: cRGD; epithelial-mesenchymal transition; ovarian cancer; uPA; vasculogenic mimicry.