Eppenberger et al. BMC Cancer 2010, 10:93 http://www.biomedcentral.com/1471-2407/10/93 R E S E A R C H A R T I C L E Open Access Role of the VEGF ligand to receptor ratio in the progression of mismatch repair-proficient colorectal cancer Manuela Eppenberger†, Inti Zlobec*†, Daniel Baumhoer, Luigi Terracciano, Alessandro Lugli 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. Background Angiogenesis, the process of developing new blood ves- sels from pre-existing vascular networks, is now a well- described mechanism leading to the initiation and main- tenance of tumours, and the promotion of metastasis at secondary sites [1]. Hypoxia is a major activator of angiogenesis in tumours [2]; the hypoxic state of cells promotes the up-regulation of a variety of cytokines and tumour suppressors, such as p53 and also of hypoxia- inducible factor 1-alpha, primarily known for its ability to activate Vascular Endothelial Growth Factor (VEGF) expression [3]. * Correspondence: izlobec@uhbs.ch † Contributed equally Institute of Pathology, University Hospital of Basel, Basel, Switzerland The VEGF family of ligands and receptors includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, platelet derived growth factor (PlGF) and VEGFR1, VEGFR2, VEGFR3 and neuropilin NP1 and NP2 [4]. The best characterized of the VEGF family members is VEGF-A, whose binding to VEGFR2 (FLK1) is the predominant mechanism through which tumour cells promote angiogenesis. VEGF-A/VEGFR2 binding activates RAS/RAF-1/MEK/ ERK phosphorylation as well as signalling through PI3K/pAKT. In response to signalling activity, up-regu- lation of downstream effectors such as mdm2, 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 prolif- eration as well as increased survival, migration and © 2010 Eppenberger et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.