Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer.
Vascular endothelial growth factor (VEGF) is a cytokine that is involved in tumor angiogenesis. Wild-type p53 (wt-p53) protein has been shown in cell lines to suppress angiogenesis through thrombospondin regulation. In this study, we immunohistochemically examined the expression of VEGF, nuclear and wild-type cytoplasmic p53, bcl-2, epidermal growth factor receptor, and c-erbB-2 oncoprotein; vascular grade; proliferation index; and extent of necrosis in non-small cell lung cancer (NSCLC). We analyzed 120 cases of early-stage NSCLCs (81 squamous cell carcinomas and 39 adenocarcinomas) treated with surgery alone (median follow-up, 63 months; range, 45-74 months). VEGF expression showed a positive association with high vascular grade (microvessel score of >75 per x250 field; P = 0.008), although about half of the LVG cases also expressed VEGF. None of the p53 antibodies examined correlated with angiogenesis. However, wt-p53 expression was inversely associated with VEGF expression, suggesting that wt-p53 is involved in the suppression of the VEGF gene. Combined analysis of VEGF, wt-p53, and microvessel counting showed that, although wt-p53 loss associates with VEGF switch-on, p53 protein may not be involved in the regulation of the angiogenic events downstream of VEGF expression. Moreover, no significant association of bcl-2 and c-erbB-2 oncoprotein expression with VEGF expression was observed. T/N stage, grade, Ki67 proliferation index, and extent of necrosis were not correlated with VEGF expression. Survival analysis showed that VEGF correlated with poor survival (P = 0.04) and was significant in node-negative cases (P = 0.03). We conclude that VEGF is an important angiogenic factor in NSCLC, its expression being dependent on wt-p53 loss.
Giatromanolaki
A
A
Department of Radiotherapy and Oncology, University Hospital of Iraklion, Crete, Greece.
Koukourakis
M I
MI
Kakolyris
S
S
Turley
H
H
O'Byrne
K
K
Scott
P A
PA
Pezzella
F
F
Georgoulias
V
V
Harris
A L
AL
Gatter
K C
KC
D000368:Aged; D000911:Antibodies, Monoclonal / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D016228:Endothelial Growth Factors / Q000032:analysis / Q000502:physiology*; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000032:analysis / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D066246:ErbB Receptors; D008222:Lymphokines; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors