MOLECULAR MECHANISMS LINKING THROMBOSIS AND ANGIOGENESIS IN CANCER

In this brief review, the authors concentrate on selected issues relat ed to the newly described role of tissue factor (TF), the major activa tor of mammalian blood coagulation, as a regulator of angiogenesis and of tumor growth and metastasis. Previously, TF had been considered st rictly as the primary activator of the coagulation cascade; however, i t has recently been demonstrated that overexpression of the TF gene in murine tumor cells leads to increased transcription of the gene for v ascular permeability factor/vascular endothelial growth factor (VEGF), a proangiogenic factor and decreased transcription of the gene for th rombospondin (TSP), an antiangiogenic factor Conversely, underexpressi on of TF leads to decreased VEGF and increased TSP transcription. When grown in mice and compared With low TF-producing tumor cells, high TF -producing tumor cells stimulate angiogenesis by approximately twofold . This effect of TF appears to be independent of its clot-promoting pr ocoagulant activity (PCA) and suggests that TF regulates the angiogeni c properties of tumor cells by altering the production of growth regul atory molecules (for example, VEGF) that can act on vascular endotheli al cells (VECs). There is substantial preliminary evidence that the re gulation of tumor angiogenesis can be mediated by TF via both fibrin c lotting-dependent and fibrin clotting-independent mechanisms. (C) 1997 , Elsevier Science Ltd.