Advances in Brief Phosphoinositide 3-Kinase Regulates Membrane Type 1-Matrix Metalloproteinase

Vasculogenic mimicry (VM) describes the unique ability of highly aggres-sive melanoma tumor cells to express endothelial cell-associated genes (such as EphA2 and VE-cadherin) and form vasculogenic-like networks when cultured on a three-dimensional matrix. VM has been described in several types of aggressive tumors, including melanoma, prostate, breast, and ovar-ian carcinomas. However, the molecular underpinnings of this phenomenon remain somewhat elusive. In this study, we examined key molecular mecha-nisms underlying VM in aggressive human cutaneous and uveal melanoma. The data reveal that phosphoinositide 3-kinase (PI3K) is an important reg-ulator of VM, specifically affecting membrane type 1 matrix metalloprotein-ase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) activity, critical in the formation of vasculogenic-like networks. Using specific inhibitors of PI3K, melanoma VM was abrogated coincident with decreased MMP-2 and MT1-MMP activity. Furthermore, inhibition of PI3K blocked the cleavage of laminin 52 chain, resulting in decreased levels of the 2 and 2x promi-gratory fragments. Collectively, these results indicate that PI3K is an impor-tant regulator of melanoma VM directly affecting the cooperative interac-tions of MMP-2, MT1-MMP, and laminin 52 chain and, thus, the remodeling of the tumor cell microenvironment. PI3K may represent an excellent target for therapeutic intervention of a novel signaling cascade underlying VM