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Differential Role of Tissue Factor Pathway Inhibitors 1 and 2 in Melanoma Vasculogenic Mimicry¹

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037 [W. R., R. J. P.]; Department of Anatomy and Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242-1109 [E. A. S., L. M. G., N. V. M., R. E. B. S., M. J. C. H.]; Department of Internal Medicine, Carver College of Medicine, University of Iowa, and Department of Veteran Affairs Medical Center, Iowa City, Iowa 52242 [R. M. W.]; and Kanagawa Cancer Center Hospital and Research Institute, Yokohama, 241-0815 Japan [Y. M.]

Vasculogenic mimicry (VM), the formation of matrix-rich vascular-like networks in three-dimensional culture corresponding with the expression of vascular cell-associated genes, and the lining of matrix-rich networks in situ, has been observed in highly aggressive and malignant melanoma. However, little is known about the molecular underpinnings of this phenomenon. On the basis of gene profiling, protein detection, and immunohistochemistry, aggressive relative to poorly aggressive melanoma showed up-regulation of tissue factor (TF), TF pathway inhibitor 1 (TFPI-1) and 2 (TFPI-2), critical genes that initiate and regulate the coagulation pathways. The procoagulant function of TF on highly aggressive melanoma is shown to be regulated by TFPI-1 but not by TFPI-2. Thus, aggressive melanoma exhibits endothelial cell-like anticoagulant mechanisms that may contribute to the fluid-conducting potential of melanoma cell-lined networks, as studied by correlative in vivo Doppler flow measurements. Antibody inhibition experiments reveal that TFPI-2 is required for VM in vitro, but plasmin is an unlikely target protease of TFPI-2. Blockade of TFPI-2 suppressed matrix metalloproteinase-2 activation, and, therefore, TFPI-2 appears to regulate an essential pathway of VM. TFPI-2 is synthesized by endothelial and tumor cells, which deposit TFPI-2 into extracellular matrices. Culturing poorly aggressive melanoma cells on three-dimensional matrix containing recombinant TFPI-2 produces some of the phenotypic changes associated with aggressive, vasculogenic melanoma cells. Thus, TFPI-2 contributes to VM plasticity, whereas TFPI-1 has anticoagulant functions of relevance for perfusion of VM channels formed by TF-expressing melanoma cells.

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