Angiogenic factor VEGF is decreased in human colorectal neoplasms showing DNA microsatellite instability

Abstract

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two important determinants of angiogenesis in human cancers. Expression of VEGF and bFGF was examined by immunohistochemistry in 120 colorectal cancers. Neoplasms were classified according to the presence or absence of microsatellite instability determined at six microsatellite loci and labelled as a high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) or microsatellite stable (MSS). Only 4/30 MSI-H cancers expressed VEGF (13 per cent), compared with 24/64 MSS cancers (38 per cent; p< 0.01). Fewer MSI-H cancers showed bFGF expression (38 per cent) than MSS cancers (53 per cent; p< 0.09). MSI-L cancers showed the same pattern as MSS cancers. Western blotting and immunohistochemistry showed that the tumour suppressor gene p53 was mutated infrequently in MSI-H cancers (8 per cent; p< 0. 001). Microvessel density counts using CD31 and UEA-1 demonstrated no difference in the number of blood vessels in MSI-H and MSS cancers. Although these results are consistent with the known role of wild-type p53 in down-regulating VEGF, no association was found between a mutation in p53 and VEGF or bFGF levels in all colonic neoplasms. This is the first evidence that MSI-H cancers may follow a different pathway to angiogenesis. The low frequency of VEGF expression amongst MSI-H cancers may partially explain why these cancers are less aggressive, with a better overall prognosis.