Expression of angiogenic VEGF-A (soluble isoforms 121, 165) and lymphangiogenic VEGF-C in colorectal cancers with micro-satellite instability.

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.)