Cooperative interactions of laminin 5 gamma 2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma

Vasculogenic mimicry describes a process where aggressive tumor cells in th ree-dimensional matrices mimic embryonic vasculogenesis by forming extracel lular matrix (ECM)-rich, patterned tubular networks. Microarray gene chip a nalyses revealed significant increases in the expression of laminin 5 (Ln-5 , gamma2 chain) and matrix metalloproteinases (MMP)-1, -2, -9, and MT1-MMP (MMP-14) in aggressive compared with poorly aggressive melanoma cells. Thes e components colocalized with developing patterned networks and antisense o ligonucleotides to the Ln-5 gamma2 chain (but not sense oligonucleotides), and antibodies to MMP-2 or MT1-MMP (but not MMP-9) inhibited the formation of these networks. Cultures which did not receive antibodies to either MMPs -2 or -14 contained the Ln-5 gamma2 chain promigratory cleavage fragments. Poorly aggressive melanoma cells seeded on collagen I matrices precondition ed by the aggressive cells formed tubular networks along the Ln-5 gamma2 ch ain-enriched tracks deposited by the aggressive cells. These results sugges t that increased expression of MMP-2 and MT1-MMP, along with matrix deposit ion of the Ln-5 gamma2 chain and/or its cleavage fragments, are required fo r vasculogenic mimicry by aggressive melanoma cells. Furthermore, the appar ent recapitulation of laminin-rich, patterned networks observed in aggressi ve melanoma patients' tissue sections by aggressive melanoma tumor cells in three-dimensional culture may also serve as a model to help identify speci fic molecular targets which could function as templates for the coordinated migration of aggressive tumor cells and their proteolytic remodeling of th e ECM and may have profound implications for the development of novel thera pies directed at the ECM to alter tumor progression.