Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor

Abstract

Tissue factor (TF), a transmembrane receptor for coagulation factor VII͞VIIa, is aberrantly expressed in human cancers. We demonstrated a significant correlation between TF and vascular endothelial growth factor (VEGF) production in 13 human malignant melanoma cell lines (r 2 ‫؍‬ 0.869, P < 0.0001). Two of these cell lines, RPMI-7951, a high TF and VEGF producer, and WM-115, a low TF and VEGF producer, were grown s.c. in severe combined immunodeficient mice. The high-producer cell line generated solid tumors characterized by intense vascularity, whereas the low producer generated relatively avascular tumors, as determined by immunohistologic staining of tumor vascular endothelial cells with anti-von Willebrand factor antibody. To investigate the structure-function relationship of TF and VEGF, a lowproducer melanoma cell line (HT144) was transfected with a TF cDNA containing the full-length sequence, a cytoplasmic deletion mutant lacking the coding sequence for the distal three serine residues (potential substrates for protein kinase C), or an extracellular domain mutant, which has markedly diminished function for activation of factor X. Cells transfected with the full-length sequence produced increased levels of both TF and VEGF. Transfectants with the full-length sequence and the extracellular domain mutant produced approximately equal levels of VEGF mRNA. However, cells transfected with the cytoplasmic deletion mutant construct produced increased levels of TF, but little or no VEGF. Thus, the cytoplasmic tail of TF plays a role in the regulation of VEGF expression in some tumor cells.

Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease

“…The cytoplasmic domain of TF seems to be essential for the production of VEGF in human gastric cancer and melanoma (Abe et al, 1999) cells. A positive feedback mechanism induces upregulation of VEGF on tumour cells, further increasing TF expression (Zhang et al, 1994).…”

“…Upregulation of tissue factor (TF), the primary initiator of the coagulation cascade, has a key role in this process (Molnar et al, 2007). In normal physiological conditions, TF, a 47 kDa transmembrane protein, is constitutively expressed by subendothelial cells (such as pericytes, smooth muscle cells and fibroblasts), whereas vascular endothelial cells (ECs) and intravascular cells do not express TF (Abe et al, 1999). Initiation of the extrinsic coagulation pathway occurs when TF is exposed to the bloodstream, either after damage to the normal integrity of the vascular EC lining or on activation of monocytes or ECs.…”

“…Furthermore, correlations of elevated TF expression with advanced stages of malignancy have been reported in different cancers, including colon (Nakasaki et al, 2002) and breast (Ueno et al, 2000), suggesting that TF may have a role in tumour progression. In addition, TF is known to contribute to tumour progression indirectly, through the role in haemostasis, and, in part, by upregulating the pro-angiogenic vascular endothelial growth factor-A (VEGF) (Zhang et al, 1994;Abe et al, 1999). VEGF, a 34 -45 kDa protein, is the most potent known stimulator of angiogenesis (the outgrowth of new capillaries from an existing vascular bed), an essential process in tumour growth, progression and metastasis (Folkman, 1995).…”

Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies

“…A crosslinked fibrin network provides a provisional proangiogenic matrix that facilitates blood vessel infiltration. Clotting-independent pathways are primarily mediated by the constitutive and aberrant expression of TF observed in many tumor cells and associated vascular endothelial cells, and can be divided into three independent, although interconnected pathways ( Figure 3) that appear to involve: (i) phosphorylation of the cytoplasmic domain of the TF receptor and subsequent downstream signaling events that occur independently of thrombin production or clot formation, and possibly even independently of ligand activation; 25 (ii) activation of intracellular signaling as a consequence of TF-FVII(a) interaction and subsequent actin reorganization and increased endothelial cell adhesion and migration; 26 and (iii) via thrombin generation, which can induce angiogenesis by cleaving the cell membrane-bound PARs, thus leading to the transcriptional activation of a number of genes that are involved in angiogenesis. 9 In vivo, PAR signaling has generally been attributed to activation by thrombin.…”

Intravital microscopy in a dorsal skinfold chamber: hemodynamics, tumor angiogenesis and inflammation

“…Particularly tissue factor, expressed in tumor cells, regulates synthesis of the endothelial cell-specific growth factor VEGF by its cytoplasmic domain. 53 Tumor-derived VEGF induces tissue factor expression in endothelial cells, resulting in enhanced thrombin formation. Thrombin is a potent mitogen of endothelial cells, which are induced to secrete growth factors and express both VEGF receptors, fetal liver kinase 1 (flk-1) and fms-like tyrosine kinase 1 (flt-1).…”