Clinical significance of vascular endothelial growth factor and Delta-like ligand 4 in small pulmonary adenocarcinoma

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The notch ligand Delta-like ligand 4 (DLL4) is induced by VEGF and acts as a negative regulator of tumor angiogenesis by reducing the numbers of non-productive sprouting vessels. Several reports have shown the prognostic role of VEGF expression in non-small cell lung cancer. However, the correlation between VEGF and DLL4 expression and their clinical significance in non-small cell lung cancer remains unclear. The aim of this study was to analyze the correlation between the expression of VEGF/DLL4 and the clinicopathological background. Fifty-eight patients with lung adenocarcinomas measuring less than 3 cm in diameter who underwent surgical resection at Kawasaki Medical School Hospital from 2008 to 2010 were enrolled in this study. The expressions of VEGF, DLL4, CD31, and Ki-67 were analyzed using immunohistochemical staining. The tumor cells were VEGF-positive in 44 patients (75.9%) and DLL4-positive in 41 patients (70.7%). No statistically significant association was observed between the patients’ characteristics and VEGF/DLL4 expression. A high VEGF expression level tended to be associated with a high DLL4 expression level (P = 0.050, r = 0.258). The mean Ki-67 index was significantly lower in the patients with high VEGF expression (9.5 vs. 18.2, P = 0.011), but no significant difference was observed when patients were compared according to their DLL4 expression levels (11.8 vs. 11.0, P = 0.804). The mean Ki-67 index was higher in the VEGFlow DLL4low patients than in the VEGFhigh DLL4high patients by a marginally significant difference (20.1 vs. 10.9 P = 0.056). The 3-year recurrence-free survival rates of the VEGFhigh/DLL4high and the VEGFlow/DLL4low patients were 83.3% and 35.7%, respectively. The prognosis of the VEGFhigh/DLL4high patients was significantly better than that of the VEGFlow/DLL4low patients (P = 0.032). To investigate the significance of the difference in tumor proliferation and prognosis between the VEGFhigh/DLL4high and the VEGFlow/DLL4low patients, we evaluated the morphologic effect of VEGF/DLL4 expression on the intratumoral capillaries by counting the number of capillaries and calculating the luminal area (μm2). No significant differences were seen between either the VEGF or DLL4 expression levels and the mean number of intratumoral capillaries or the luminal area (μm2). In conclusion, VEGFlow/DLL4low patients with small pulmonary adenocarcinoma had a significantly poorer prognosis, although no significant difference in a morphological evaluation of the capillaries was seen between VEGFhigh/DLL4high and VEGFlow/DLL4low patients. doi:10.11482/KMJ-E40(1)23 (Accepted on October 22, 2013)

Yasuda K, et al