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Background and Objectives: Colorectal cancers (CRC) with high-level micro-satellite instability (MSI-H) show reduced metastatic potential and better prognosis compared to stage-matched stable (MSS) cancers. Angiogenesis/lymphangiogenesis, central to tumour growth and spread, is mediated by vascular endothelial growth factor (VEGF) cytokines, but little is known of their relationship to MSI., Methods: In this study, 67 sporadic CRC with identified MSI status, and 8 samples of normal colon were analysed for VEGF-A soluble isoforms (VEGF-121/VEGF-165) and VEGF-C gene transcription (by RT-PCR and scanning densitometry), and blood vessel density (BVD; measuring angiogenesis) and VEGF-C protein expression (measuring lymphangiogenesis)., Results: Compared to normal colon, VEGF-165 transcription was reduced (P < 0.05), but VEGF-121 transcription was higher in MSS (P < 0.06) and MSI-L (P < 0.01) cancers (but similar in MSI-H). VEGF-165 transcription was unrelated to MSI, but VEGF-121 transcription was elevated in MSI-L (P < 0.06). There was a weak inverse correlation with VEGF-121 transcription and Dukes stage (P < 0.09), and with BVD and MSI (P < 0.09). With a singular di-nucleotide loci mutation (MSI-L), VEGF-121 (P < 0.03) and VEGF-C (P < 0.04) transcription was elevated., Conclusions: MSI-H cancers have reduced angiogenic/lymphangiogenic potential, and transcription of VEGF-121 may be important in early growth and spread of CRC. Elevated VEGF-121 and VEGF-C transcription with singular di-nucleotide mutations may aid in the identification of distinct MSI-L cancers., (2005 Wiley-Liss, Inc.)

Micro-satellite instability (MSI) is relevant in the management of colorectal cancers (CRC) and relies on analysis of gene mutations, or production of the proteins involved in DNA mismatch repair (e.g. MLH1, MSH2). p53 mutation is also relevant in MSI, but high-level CRC (MSI-H) demonstrate fewer mutations than low-level (MSI-L) or stable (MSS) cancers. Recently, the importance of gene activity (transcription) in MSI has been identified, where rather than being mutated genes have been downregulated. In this study, 67 sporadic CRC and eight samples of normal bowel were analysed for MSI status (by SSCP) and levels of MLH1, MSH2 and p53 gene transcription (by RT-PCR and scanning densitometry). Micro-satellite instability correlated with gender and site, with more MSI-H CRC in females (P<0.02) and in the right colon (P<0.04). In MSI-H, p53 transcription was markedly reduced (P<0.003). Compared to normal bowel, MLH1 transcription was elevated in all cancers (P<0.01), while MSH2 transcription was elevated only in MSI-H (P<0.04). There was a direct correlation between MLH1 and MSH2 transcription (P<0.001). Although fewer mutations are reported in MSI-H than MSI-L/MSS, these results suggest that reduced p53 transcription might account for decreased tumour suppression in MSI-H. The direct correlation between MLH1 and MSH2 transcription suggests that control of these genes might be coordinated.