Abstract
BackgroundThe VEGF family of ligands and receptors are intimately involved in tumor angiogenesis, lymphangiogenesis and metastasis. The evaluation of VEGF ligand/receptor ratios may provide a more profound understanding of the involvement of these proteins in colorectal tumour progression. The aim of this study was to elucidate the role of the VEGF ligand/receptor ratios on tumour progression and metastasis in patients with mismatch repair-proficient colorectal cancer.MethodsImmunohistochemistry for VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGFR1, VEGFR2 and VEGF3 was carried out on 387 mismatch repair-proficient colorectal cancers using a tissue microarray. Evaluation of immunoreactivity was performed semi-quantitatively and the ligand/receptor expression ratio was obtained.ResultsAn increased VEGF-A/VEGFR1 ratio, VEGF-A and VEGFR1 was linked to the presence of peritumoral lymphocytic inflammation at the invasive front (p = 0.032; p = 0.005; p = 0.032, respectively). VEGFR1 expression was related to poorer outcome in multivariable analysis with pT stage, pN stage, vascular invasion, and post-operative therapy. A higher ratio of VEGF-A/VEGFR2 was linked to advanced TNM stage (p = 0.005) while VEGF-A and VEGFR2 were elevated in tumours with an infiltrating tumour growth pattern (p = 0.006; p = 0.014; p = 0.006). No effect of VEGF-A/VEGFR2, VEGF-A or VEGFR2 on survival time was noted.ConclusionsOur findings highlight an involvement of VEGF-A, VEGR1 and VEGFR2 in events occurring at the invasive tumour front and a potential prognostic role of VEGFR1 expression in mismatch repair-proficient colorectal cancers. The VEGF-A ligand to VEGFR1 or VEGFR2 ratio may represent an alternative evaluation system for identifying patients with poorer clinical outcome.
Highlights
The Vascular Endothelial Growth Factor (VEGF) family of ligands and receptors are intimately involved in tumor angiogenesis, lymphangiogenesis and metastasis
VEGF ligand/receptor ratios (Tables 2 and 3) An increased VEGF-A/VEGFR1 ratio was observed in patients with tumours presenting conspicuous peritumoural lymphocytic inflammation at the invasive front (p = 0.032)
The ratio of VEGF-A to VEGFR1 and VEGFR2 as well as the ratio of VEGF-C/VEGFR2 demonstrated the most interesting effects of these angiogenic proteins on progression and survival. These results are similar to those reported by Hanrahan et al who investigated VEGF ligands and their receptors at the mRNA level in normal, adenoma and colorectal carcinoma [20]. They suggest that VEGF-A and VEGF-B may be responsible for the initiation of tumour whereas VEGFA and VEGF-C are further expressed in order to maintain disease progression
Summary
The VEGF family of ligands and receptors are intimately involved in tumor angiogenesis, lymphangiogenesis and metastasis. In response to signalling activity, up-regulation of downstream effectors such as mdm, p53, p27, endothelial nitric oxide, and Bcl-2 can occur as well as inhibition of pro-apoptotic proteins caspase-9 and APAF-1. The consequences of this binding are increased vascular permeability, enhanced endothelial cell proliferation as well as increased survival, migration and invasion of tumour cells. VEGFA seems to induce much weaker tyrosine kinase activity in VEGFR1 possibly because of an inhibitory sequence in the juxtamembrane domain that represses VEGFR1 activity [6] In keeping with this observation, a model for VEGFR1 has been developed whereby it could act as a decoy receptor to modulate angiogenesis through its ability to sequester VEGFA thereby reducing signaling through VEGFR2. VEGF-C along with VEGF-A and a variety of pro-angiogenic cytokines have been shown to be released from tumour associated macrophages, whose infiltration is thought to be, at least in part, responsible for the angiogenic switch in tumours whereby the balance of pro- and anti-angiogeneic factors favour a pro-angiogenic phenotype [8,9,10]
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