VASCULAR ENDOTHELIAL GROWTH-FACTOR AND NITRIC-OXIDE SYNTHASE EXPRESSION IN HUMAN LUNG-CANCER AND THE RELATION TO P53

Vascular endothelial growth factor (VEGF) expression and mutations of cancer-related genes increase with cancer progression. This correlatio n suggests the hypothesis that oncogenes and tumour suppressors regula te VEGF, and a significant correlation between p53 alteration and incr eased VEGF expression in human lung cancer was reported recently. To f urther examine this hypothesis, we analysed VEGF protein expression an d mutations in p53 and K-ras in 27 non-small-cell lung cancers (NSCLC) : 16 squamous cell, six adenocarcinomas, one large cell, two carcinoid s and two undifferentiated tumours. VEGF was expressed in 50% of the s quamous cell carcinomas (SCC) and carcinoids but none of the others. p 53 mutations occurred in 14 tumours (52%), and K-ras mutations were fo und in two adenocarcinomas and one SCC; there was no correlation betwe en the mutations and VEGF expression. As nitric oxide also regulates a ngiogenesis, we examined NOS expression in NSCLC. The Ca2+-dependent N OS activity, which indicates NOS1 and NOS3 expression, was significant ly reduced in lung carcinomas compared with adjacent non-tumour tissue (P < 0.004). Although the Ca2+-independent NOS activity, which indica tes NOS2 expression, was low or undetectable in non-tumour tissues and most carcinomas, significant activity occurred in three SCC. In summa ry, our data do not show a direct regulation of VEGF by p53 in NSCLC. Finally, we did not find the up-regulation of NOS isoforms during NSCL C progression that has been suggested for gynaecological and breast ca ncers.