Eppenberger et al. BMC Cancer 2010, 10:93 http://www.biomedcentral.com/1471-2407/10/93 Table 2 VEGF-A/VEGFR1, VEGF-A/VEGFR2, VEGF-B/VEGFR1, and VEGF-C/VEGFR2 ratios and association with clinico- pathological features in mismatch repair-proficient colorectal cancer. VEGF-A/VEGFR1 P-value VEGF-A/VEGFR2 P-value VEGF-B/VEGFR1 P-value VEGF-C/VEGFR2 P-value TNM stage Tumour grade Vascular invasion Tumour border configuration PTL infiltration I+II III IV G1-2 G3 Absent Present PM IM Absent Present 13.7 ± 32.6; 1.0 13.0 ± 31.7; 1.0 5.2 ± 19.7; 1.0 10.7 ± 29.2; 1.0 13.5 ± 32.2; 1.0 13.2 ± 32.2; 1.0 6.48 ± 22.0; 1.0 12.4 ± 31.2; 1.0 9.83 ± 27.6; 1.0 9.73 ± 27.6; 1.0 17.5 ± 36.6; 1.0 0.198 0.704 0.276 0.211 0.032 1.63 ± 8.6; 1.0 0.66 ± 0.4; 0.95 3.85 ± 16.3; 1.0 2.05 ± 10.6; 1.0 0.73 ± 0.4; 0.95 2.2 ± 11.3; 1.0 0.78 ± 0.36; 0.98 1.35 ± 6.3; 1.0 2.28 ± 12.2; 0.95 1.56 ± 8.4; 1.0 2.83 ± 13.6; 1.0 0.005 0.179 0.38 0.006 0.074 11.2 ± 27.2; 1.0 8.1 ± 23.2; 1.0 5.9 ± 20.0; 1.0 8.0 ± 22.9; 0.98 12.9 ± 29.7; 1.0 10.7 ± 26.9; 1.0 4.28 ± 15.2; 0.95 9.8 ± 25.2; 1.0 7.76 ± 23.2; 0.95 8.09 ± 23.5; 1.0 12.3 ± 27.5; 0.87 0.867 0.956 0.078 0.244 0.356 Mean ± SD, median values. Kruskal Wallis or Wilcoxon Rank Sum Test. PM = pushing/expanding margin; IM = infiltrating margin; PTL = peritumoral lymphocytic. Increased expression of VEGFR1 was linked to poorer outcome, while the remaining established prognostic factors also maintained their independent effect on out- come (Table 4). VEGFR1 expression also was related to poorer prognosis after adjusting additionally for post- operative adjuvant therapy. The ratio of VEGF-A/VEGFR2 was linked to TNM stage (p = 0.005). The average VEGF-A/VEGFR2 ratio was 3.85 in metastatic stage IV cases compared to 0.66 in stage III and 1.63 in stages I and II. Increased expression of this ratio was again observed in patients with tumours showing an infiltrating tumour growth pattern (p = 0.006). When evaluating VEGF-A or VEGFR2 expression separately and their relationship to the tumour border configuration, a strong loss of VEGF-A (p = 0.014) and VEGFR2 expression in tumours with infiltrating margin (p = 0.006) was observed. However, no effect of VEGF- A/VEGFR2 or VEGFR2 on survival time was noted. Decreased expression of VEGF-C/VEGFR2 was observed in more advanced TNM stage (p = 0.003). However, the remaining VEGF-ligand/receptor ratios were not related to either clinico-pathological features nor with survival in either metastatic and non-metastatic patients. Discussion This work appears to be the first to evaluate in a single study the immunohistochemical importance of four VEGF ligands with their corresponding receptors in an expression ratio in colorectal cancer. The findings here support a role, not only for VEGF-A, VEGFR1 and VEGFR2 in tumour progression but most importantly of a potential prognostic role of VEGFR1 expression in mismatch repair-proficient colorectal cancer. 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 pro- gression 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 nor- mal, adenoma and colorectal carcinoma [20]. In their study, they suggest that VEGF-A and VEGF-B may be responsible for the initiation of tumour whereas VEGF- A and VEGF-C are further expressed in order to main- tain disease progression. They observed a significant correlation between VEGF-A and tumour size but not with tumour stage, lymphovascular invasion or metasta- sis. In addition, they document a significant link between VEGFR1 expression and tumour grade and Page 6 of 10 0.003 0.06 0.412 0.326 0.235 2.6 ± 9.3; 0.8 0.58 ± 0.38; 0.68 1.95 ± 8.8; 0.84 1.51 ± 8.2; 0.79 0.58 ± 0.4; 0.65 1.6 ± 8.9; 0.75 0.65 ± 0.38; 0.75 1.2 ± 5.7; 0.79 1.48 ± 9.04; 0.75 1.01 ± 4.5; 0.78 2.79 ± 14.7; 0.75