thromboplastin and Uveal-Neoplasms

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.

Topics: Animals; CHO Cells; Cricetinae; Glycoproteins; Humans; Lipoproteins; Melanoma; Mice; Mice, Nude; Neovascularization, Pathologic; Skin Neoplasms; Thromboplastin; Transplantation, Heterologous; Uveal Neoplasms

To study the expression of angiogenic factors Cyr61 and tissue factor (TF) in uveal melanoma and its correlation with blood vessel density.. Suppression subtractive hybridization was used to identify genes that are differentially expressed between cell lines of uveal melanoma and normal uveal melanocytes. Expression of these genes was subsequently verified in primary uveal melanomas and correlated with the number of blood vessels in archival specimens by immunohistochemical analysis.. Cyr61 and TF are expressed at elevated levels in cell lines of uveal melanoma compared with normal uveal melanocytes. Duplication of a region of chromosome arm 1p, encompassing the genes encoding Cyr61 and TF, was observed in the melanoma cell line used in the initial subtractive hybridization. Both genes are also expressed in primary uveal melanomas, and a correlation was found between expression of TF and the number of blood vessels in archival specimens.. Cyr61 and TF may contribute to the angiogenic phenotype associated with uveal melanoma. A region of chromosome arm 1p also may contain oncogenes or tumor suppressor genes pertinent to the origins of this type of ocular tumor.. New immunotherapies have been devised for the treatment of cancer based on the expression of TF. Similar approaches may be effective in treating uveal melanoma.

Topics: Blotting, Western; Chromosomes, Human, Pair 1; Cysteine-Rich Protein 61; Cytogenetics; Endothelial Growth Factors; Humans; Immediate-Early Proteins; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Intercellular Signaling Peptides and Proteins; Lymphokines; Melanoma; Neovascularization, Pathologic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboplastin; Tumor Cells, Cultured; Uveal Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors