Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression

Angiogenesis is an essential requirement for the development, progression a nd metastasis of malignant tumours. Studies on transgenic mouse models have shown that angiogenesis begins in the pre-malignant phase of oncogenesis, when dysplastic lesions acquire an increased microvasculature, To investiga te the relationship between the expression of vascular endothelial growth f actor (VEGF) and colorectal tumour progression, we have studied VEGF expres sion level and splice variant pattern by semi quantitative RT-PCR and the c ellular source of VEGF expression by in situ hybrization (ISH) in a range o f lesions that modelled the tumour-development pathway from normal colon to invasive colorectal adenocarcinomas. Colonic adenomas showed a statistical ly significant up-regulation of VEGF expression over normal tissues, with a further increase during the development of adenocarcinomas, Tumour cells f ormed the major source of VEGF expression, with a minor contribution from m ononuclear cells in the tumour stroma and enhanced expression in tumour cel ls around necrotic regions. The comparable expression level in both the in site and invasive components in the same tumours indicated that a high VEGF expression capacity had been acquired prior to establishment of the invasi ve phenotype, Our findings support activation of VEGF as the molecular basi s for the discrete induction of angiogenesis in the pre-malignant phase of colorectal tumour development. (C) 1999 Wiley-Liss, Inc.