Role of the VEGF ligand to receptor ratio in the progression of mismatch repair-proficient colorectal cancer

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Figure 1A-N. Different colorectal cancer samples with negative and positive staining for VEGF ligands (cytoplasmic) and receptors (membraneous and/or cytoplasmic): VEGFA+ (A), VEGFA- (B), VEGFB+ (C), VEGFB- (D), VEGFC+ (E), VEGFC- (F), VEGFD+ (G), VEGFD- (H), VEGFR1+ (I), VEGFR1- (J), VEGFR2+ (K), VEGFR2- (L), VEGFR3+ (M) and VEGFR3- (N).

Figure 2

Study Design. 489 unselected patients were initially entered into this study. After tissue microarray construction, immunohistochemistry for VEGF ligands and receptors, 102 mismatch repair-deficient cases were excluded. Analysis of VEGF ligand/receptor ratio with clinico-pathological features and survival was performed on the remaining 387 mismatch repair-proficient cases.

Figure 3

Differences in mean VEGF ligand and receptor expression in normal colorectal mucosa in comparison to colorectal cancers. Standard error bars are shown.