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 and 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 investigate the relationship between the expression of vascular endothelial growth factor (VEGF) and colorectal tumour progression, we have studied VEGF expression level and splice variant pattern by semi-quantitative RT-PCR and the cellular source of VEGF expression by in situ hybrization (ISH) in a range of lesions that modelled the tumour-development pathway from normal colon to invasive colorectal adenocarcinomas. Colonic adenomas showed a statistically significant up-regulation of VEGF expression over normal tissues, with a further increase during the development of adenocarcinomas. Tumour cells formed the major source of VEGF expression, with a minor contribution from mononuclear cells in the tumour stroma and enhanced expression in tumour cells around necrotic regions. The comparable expression level in both the in situ and invasive components in the same tumours indicated that a high VEGF expression capacity had been acquired prior to establishment of the invasive phenotype. Our findings support activation of VEGF as the molecular basis for the discrete induction of angiogenesis in the pre-malignant phase of colorectal tumour development.