Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): Correlation with angiogenesis and survival

The formation of new vessels (angiogenesis) is essential for primary tumour growth and metastasis and is induced by several angiogenic factors, includ ing vascular endothelial growth factor (VEGF). The microvascular density (M VD) in tumours was assessed and the expression of VEGF and its receptors VE GF-R1-Flt1 and VEGF-R2-KDR/Flk1 was investigated in the different cellular compartments in vivo, in order to establish their interrelationship and the ir prognostic influence. Immunohistochemical study of 69 stage I-II non-sma ll cell lung carcinomas (NSCLCs) was performed on paraffin sections with CD 34 antibody to estimate MVD, using a Chalkley eye-piece graticule and VEGF, VEGF-R1, and VEGF-R2 antibodies. There was strong expression of VEGF and i ts receptors in tumour cells, endothelial cells, and stromal fibroblasts. I n tumour cells, the level of VEGF was correlated with that of VEGF-R1 (p=0. 018) but not that of VEGF-R2. In fibroblasts, high expression of VEGF was c orrelated with that of VEGF-R1 (p=0.0001) and VEGF-R2 (p=0.0001). In endoth elial cells, expression of VEGF was correlated with that of VEGF-R1 (p<0.00 01) and VEGF-R2 (p=0.04). The level of VEGF in fibroblasts was correlated w ith that of VEGF-R1 (p=0.0028) and VEGF-R2 (p=0.01) in endothelial cells. T here was no correlation between the level of MVD and that of VEGF or VEGF-R 1 or VEGF-R2. Neither the level of MVD, nor the level of expression of VEGF and VEGF receptors in any compartment influenced the patient's survival. I n conclusion, although angiogenesis is essential for tumour growth, this st udy failed to demonstrate that MVD, VEGF, VEGF-R1, and VEGF-R2 are prognost ic markers for stage I-II NSCLC. VEGF, however, might act as a direct autoc rine growth factor for tumour cells via VEGF-R1 and angiogenesis could be p romoted in a paracrine loop, where VEGF is produced by fibroblasts and tumo ur cells and then binds to endothelial cells via induced VEGF receptors. VE GF and its receptors thus appear as relevant therapeutic targets in NSCLC. Copyright (C) 1999 John Wiley & Sons, Ltd.