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

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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 VEGF_<low> DLL4_<low> 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 VEGF_<high>/DLL4_<high> and the VEGF_<low>/DLL4_<low> patients were 83.3% and 35.7%, respectively. The prognosis of the VEGF_<high>/DLL4_<high> patients was significantly better than that of the VEGF_<low>/DLL4_<low> patients (P = 0.032). To investigate the significance of the difference in tumor proliferation and prognosis between the VEGF_<high>/DLL4_<high> and the VEGF_<low>/DLL4_<low> 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 (μm^2). No significant differences were seen between either the VEGF or DLL4 expression levels and the mean number of intratumoral capillaries or the luminal area (μm^2). In conclusion, VEGF_<low>/DLL4_<low> patients with small pulmonary adenocarcinoma had a significantly poorer prognosis, although no significant difference in a morphological evaluation of the capillaries was seen between VEGF_<high>/DLL4_<high> and VEGF_<low>/DLL4_<low> patients.
川崎医科大学の論文

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

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