Tumour necrosis factor- α and transforming growth factor- β are significantly associated with better prognosis in non-small cell lung carcinoma: putative relation with BCL -2-mediated neovascularization

Recent in vivo and in vitro studies have demonstrated a wide spectrum of biologic activities of cytokines in the pathogenesis and progression of malignancy. Tumour necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) have emerged as two of the many host-derived mediators that seem to interfere with both antiproliferative and tumorigenic effects in malignant tumours including lung cancer. However, their association with tumour prognosis or prognostic factors has not yet been completely clarified. In this study, we assessed TNF-α and TGF-β mRNA expression by RT-PCR technique in 61 NSCLC samples, demonstrating the presence of TNF-α and TGF-β mRNA in 55.74% and 45.9% of cases, respectively. We also evaluated the expression of the two distinct transmembrane TNF receptors. TNFR-I and TNFR-II, with a PCR-positive signal in 70.49% and 65.57% of cases, respectively. In 49 of the 61 cases, we evaluated the prognostic impact of the two growth-inhibiting factors using the Kaplan–Meier analysis. In the univariate analysis patients without nodal metastatic involvement (P = 0.02), less advanced tumour stage (P = 0.02) or TNF-α and TGF-β positive cancers (P = 0.01 and P = 0.03) showed a favourable prognosis in terms of overall survival. Since our previous studies demonstrated a significant association between NSCLC behaviour, neoangiogenesis and bcl -2 expression, we investigated the putative relation between TNF-α and TGF-β on the one hand, and vascular count (as a measure of tumour angiogenesis) and bcl -2 protein expression, on the other hand. Our results showed a significant direct association between TNF-α and bcl -2 (P = 0.05) and an inverse association between TNF-α and microvessel count (P = 0.03). Moreover, as previously demonstrated, we observed a significant inverse correlation between bcl -2 protein expression and vascular count (P = 0.05), suggesting that the favourable effect of TNF-α on clinical outcome may be related to a bcl -2-mediated low neovascular development. © 2000 Cancer Research Campaig

Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression.

Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation

Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas

The vascular endothelial growth factor (VEGF) has been shown to be strictly related to vascular permeability and endothelial cell growth under physiological and pathological conditions. In tumour development and progression, VEGF plays a pivotal role in the development of the tumoral vascular network, and useful information in the progression of human cancer can be obtained by analysing the vascular endothelial growth factor expression of the tumours. In this study, we investigated the vascular endothelial growth factor transcript expression in non-small-cell lung carcinomas to evaluate the significance of this factor in a group of cancers in which the vascular pattern has been shown to significantly affect progression. Surgical samples of 42 patients with NSCLC were studied using reverse transcription polymerase chain reaction (PCR) analysis and in situ hybridization. Thirty-three out of 42 cases (78.6%) showed VEGF transcript expression predominantly as transcripts for the secretory forms of VEGF (isoforms 121 and 165). In situ hybridization, performed on 24 out of 42 samples, showed that the VEGF transcript expression was in several cases present in the cytoplasm both of neoplastic and normal cells, even if the VEGF mRNA was less expressed in the corresponding non-tumoral part. The VEGF 121 expression was associated with hilar and/or mediastinal nodal involvement (P = 0.02), and, taken together, the VEGF isoforms were shown to significantly influence overall (P = 0.02) and disease-free survival (P = 0.03). As a regulator of tumour angiogenesis, VEGF may represent a useful indicator of progression and poor prognosis in non-small-cell lung carcinomas. © 1999 Cancer Research Campaig