bcl-2 and c-erbB-2 proteins are involved in the regulation of VEGF and of thymidine phosphorylase angiogenic activity in non-small-cell lung cancer

Tumour angiogenesis has been recently recognised as one of the most importa nt prognostic factors in lung cancer. Although a variety of angiogenic fact ors have been identified, the angiogenesis process remains poorly understoo d. Bcl-2, c-erbB-2 and p53 are well-known oncogenes involved in non-small-c ell lung cancer pathogenesis. A direct correlation of thymidine phosphoryla se (TP) and of vascular endothelial growth factor (VEGF) with intratumoural angiogenesis has been reported. In the present study we investigated the p ossible regulatory role if bcl-2, c-erB-2 proteins in angiogenesis and in V EGF and TP expression in non-small-cell lung cancer. Two hundred sixteen sp ecimens from T1,2-N0,1 staged patients treated with surgery alone were immu nohistochemically examined. Bcl-2 and c-erbB-2 were significantly inversely related to each other (P = 0.04) and both were inversely associated with m icrovessel density (P < 0.02). High TP and VEGF reactivity was statisticall y related to loss of bcl-2 expression (P < 0.01). A significant co-expressi on of c-erbB-2 with TP was noted (P = 0.01). However, TP expression was rel ated to high angiogenesis only in cases with absence of c-erB-2 expression (P < 0.0001). c-erbB-2 expression in poorly vascularised tumours was linked with poor outcome (P = 0.03). The present study provides strong evidence t hat the bcl-2 gene has a suppressive function over genes involved in both a ngiogenesis (VEGF and TP) and cell migration (c-erbB-2) in NSCLC. TP and c- erbB-2 proteins are significantly, and often simultaneously, expressed in b cl-2 negative cases. However, expression of the c-erbB-2 abolishes the TP-r elated angiogenic activity. Whether this is a result of a direct activity o f the c-erbB-2 protein or a consequence of a c-erbB-2-related immune respon se remains to be further investigated.