Tissue Factor Expression in Non-small Cell Lung Cancer: Relationship with Vascular Endothelial Growth Factor Expression, Microvascular Density, and K-ras Mutation

Abstract

Tissue factor (TF) is the physiological trigger of blood coagulation, but it could also have an important role in cancer by regulating VEGF expression and angiogenesis. TF expression was studied by real-time PCR in lung tumors of 64 patients with non-small-cell lung cancer (NSCLC) and by immunohistochemical analysis. The gene expression of two VEGF isoforms, VEGF165 and VEGF189, was also evaluated. Microvascular density (MVD) was studied by measuring Von Willebrand Factor (VWF) mRNA levels and by immunohistochemistry using an anti-CD34 antibody. TF mRNA levels were significantly lower than in corresponding non-affected lung tissues. However, TF expression was higher in T3-T4 tumors and this result was confirmed by immunohistochemistry. VEGF189 mRNA levels were ten times higher than those of VEGF165 and well correlated with TF mRNA levels. MVD was lower in the inner part of tumors than in the adjacent non-affected lung without being related to TF expression. Finally, codon 12 K-ras mutation was found in 8 lung carcinomas, and higher TF and VEGF189 mRNA levels were measured in mutated tissues (p < 0.001). These results suggest that high TF expression in lung tumors may result from K-ras mutation and contribute to NSCLC progression, probably via mechanisms other than angiogenesis.