The 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.

Immunohistochemistry 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.

An 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.

Our 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.