Expression of angiogenic VEGF-A (soluble isoforms 121, 165) and lymphangiogenic VEGF-C in colorectal cancers with micro-satellite instability.
OBJECTIVE
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.
Hollingsworth
Simon J
SJ
Colorectal Unit, Department of Surgery, Royal Free and University College Medical School, Charles Bell House, London, United Kingdom. s.hollingsworth@ucl.ac.uk
Drye
Elizabeth R
ER
Tou
Samson I H
SI
Boulos
Paul B
PB
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000235:genetics; D018895:Microsatellite Repeats; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000235:genetics*
D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C