title: Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma.
abstract: The angiogenic factor vascular endothelial growth factor-D (VEGF-D) isa ligand for VEGF receptor-3 (VEGFR-3/Flt-4) and receptor-2 (VEGFR-2/KDR)and is implicated in the development of lymphatic vessels and promotion of lymphatic metastases. We assessed the expression of VEGF-D and VEGFR-3 in relation to microvessel density (MVD) in colorectal carcinomas (CRC), adenomas, and adjacent normal tissue by immunohistochemistry on consecutive archival sections. VEGF-D was detected in malignant and benign epithelium and in some smooth muscle of the colorectum. High-grade VEGF-D expression was observed frequently (74%) in CRC compared with adenomas (0%) and adjacent normal mucosa (22%). High-grade VEGF-D expression was not correlated with MVD, Dukes' stage (A to C), or tumor differentiation, but was associated with lymphatic involvement and patient survival. By multivariate analysis, VEGF-D expression was found to be an independent prognostic factor for both disease-free and overall survival. VEGFR-3 expression was detected in a subset of vessels, typically thin-walled and devoid of RBCs, in 89% of CRC cases examined. VEGFR-3-positive vessel densities increased progressively from normal mucosa to adenomas and carcinomas and were correlated with MVD, but not with Dukes' stage (A to C), tumor differentiation, or VEGF-D expression. VEGFR-3 expression was spatially associated with macrophage-rich inflammatory infiltrates, which were significantly more frequent among VEGFR-3-positive cases. We conclude that VEGF-D expression, but not that of its receptor VEGFR-3, is an independent prognostic indicator in CRC. VEGF-D expression may be associated with disease outcome through the promotion of lymphatic involvement/metastases.
authors.affiliation: University of Nottingham Laboratory of Molecular Oncology, Cancer Research Campaign Department of Clinical Oncology, United Kingdom.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: White
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hewett
authors.forename: Dennis
authors.initials: D
authors.lastname: Kosuge
authors.forename: Thomas
authors.initials: T
authors.lastname: McCulloch
authors.forename: Berndt C
authors.initials: BC
authors.lastname: Enholm
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: J Clifford
authors.initials: JC
authors.lastname: Murray
mesh_terms: D000236:Adenoma / Q000378:metabolism; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3
chemical_list: D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042643:Vascular Endothelial Growth Factor D; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3