Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma

We have investigated the hypothesis that nitric oxide synthase (NOS2), cycl ooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) protein levels individually demonstrate a direct correlation with microvessel densi ty (MVD) and clinical outcome in human non-small cell lung cancer (NSCLC), Furthermore, we hypothesized that MVD may explain the propensity of certain histological lung cancer subtypes for early metastasis via a hematological route, Immunohistochemically, we studied the protein expression levels of NOS2, COX2, and VEGF and MVD by counting: CD31-reactive blood vessels (BVs) in 106 surgically resected NSCLC specimens. NOS2, COX2, and VEGF immunorea ctivity were observed in 48, 48, and 58%, respectively, of the study subjec ts, and their levels correlated with MVD at the tumor-stromal interphase (P less than or equal to 0.001). More adenocarcinomas and large cell carcinom as displayed overexpression of NOS2 when compared with squamous cell carcin oma (SCC; 0.44; P < 0.001), NOS2 and COX2 levels were found to correlate po sitively with VEGF status (r = 0.44; P < 0.001, 0.01, and 0.03, respectivel y). These results attest to the significant interaction of these factors in the angiogenesis of NSCLC. Although neither angiogenic factors nor MVD cor related with patient survival, the latter correlated with tumor clinical st age in both squamous (SCC; 73 BVs/mm(2)) and non-SCC (78 BVs/mm(2)) tumors. These results indicate that angiogenesis is a complex process that involve s multiple factors including NOS2, COX2, and VEGF. Furthermore, the role of angiogenesis in the biology of various histological lung cancer types may be different. The complexity of angiogenesis may explain the modest results observed in antiangiogenesis therapy that target a single protein.