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

Abstract

Summary 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 univaiiate 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 interrelationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation.

p53 and angiogenesis in non-small-cell lung cancer

“…Again, p53 expression was not associated with TP expression. The interesting recent observation (Fontanini et al, 1997) that p53 nuclear expression correlates with angiogenesis and survival is not in accordance with our previously published results. The method of this paper considered microvessel counting in one focus of high (factor VIII assessed) vascularization while the mean score of p53-positive cells was assessed in five fields.…”

“…l) 1995;Kwa et al, 1996;Nishio et al, 1996) and others that find an association between p53 alterations and a favourable behaviour. However, several other studies, which evaluated both p53 mutations and p53 nuclear overexpression, have underlined a strong statistical association between p53 alterations and poor prognosis in this type of cancer (Quinlan et al, 1992;Horio et al, 1993;Mitsudomi et al, 1993;Fontanini et al, 1995a;Harpole et al, 1995;Dalquen et al, 1996;Irie et al, 1996; Dosaka-Akita et al, 1997; Fontanini et al, 1997, Fukuyama et al, 1997, stimulating further investigation in this field. As regards the discrepancies that arise between these studies, we have identified some possible causes:…”

The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis

“…Seven of the articles Fontanini et al, 1996Fontanini et al, , 1997bFontanini et al, , 1998aHarpole et al, 1996;Takanami et al, 1999;D'Amico et al, 2000) were excluded because identical cohorts of patients were included in other selected publications.…”

Vascular endothelial growth factor in the serum of patients with non-small cell lung cancer: correlation with platelet and leukocyte counts

“…Methods: Using enzyme-linked immunosorbent assay, the levels of VEGF were determined in serum from 41 patients with untreated NSCLC (Stage: IIB,3; IIIA,6; IIIB,17; IV,15; Histology: squamous cell carcinoma,18; adenocarcinoma. 14; undetermined,9). Results: The median VEGF level was 312 pg/ml, ranging from 70 to 1440 pg/ml.…”

“…It is a soluble dimeric 34-46 kDa protein which has been implicated in endothelial cell proliferation and migration, increased vascular permeability, and stromal degradation through the activation of proteolytic enzymes [2,[4][5][6]. VEGF expression has been demonstrated in a large variety of human malignancies including breast, lung, colorectal, bladder, and ovarian cancer [2,[6][7][8][9][10][11][12][13][14][15][16]. In non-small cell lung cancer (NSCLC), expression of VEGF has been reported in 50-95% of cases [8-10,12,14 -16].…”