Vascular Endothelial Growth Factor D (VEGF-D) is a novel Independent Prognostic Marker for Survial in Gastric Cancer

Abstract

Aims: The angiogenic factor VEGF-D and its close homologue VEGF-C are ligands for VEGF receptor 3 (VEGFR–3/flt4) and have been implicated in lymphatic development and metastases. The pathobiological role of VEGF-D in gastric cancer, whose clinical outcome is critically determined by its lymphatic spread, however, is unclear. Aim: Characterization of VEGF-D, VEGF-C and VEGFR–3 expression in gastric adenocarcinomas and correlation of findings with clinicopathological characteristics. Methods: VEGF-D, VEGF-C and VEGFR–3 were detected by immunohistochemistry (IHC), real time RT-PCR and/or in situ hybridization in R0-resected primary gastric adenocarcinomas (n=91), corresponding non-cancerous tissues and lymph node metastases. Blood and lymphatic vessels were identified by IHC using antibodies recognizing appropriate marker molecules (CD31, Lyve1, podoplanin) on consecutive tissue sections. Results were correlated with clinicopathological characteristics employing the SPSS 11.0 software. Results: VEGF-D was detected in 69% of proximal and 66% of distal gastric cancers, whereas VEGF-C was found in 59% proximal and 46% distal cancers. „Normal“ tissues were in 16% VEGF-D positive and consistently negative for VEGF-C. VEGF-D and –C were primarily detected in cancer cells, and to a lesser extend in endothelial, inflammatory, and/or smooth muscle cells. VEGFR–3 was mainly found in lymphatic endothelial cells, but was also detected in tumor blood vessel endothelium. VEGF-D was correlated with lymphatic invasion, lymphatic metastases and age >59 years as well as shorter cancer-related and disease-free survival (p<0.05). Cox multivariate regression analysis qualified VEGF-D as independent prognostic parameter for cancer-related (p<0.016) and disease-free survival (p<0.022). Conclusions: Here we describe for the first time the expression pattern of VEGF-D in gastric cancer and establish VEGF-D as novel prognostic survival marker in this cancer entity. Our results are in line with the proposed lymphangiogenic effects of VEGF-D and suggest that VEGF-D is involved in the molecular process promoting the lymphatic spread of gastric cancers. Our results may further help to define and identify (a) subgroup(s) of gastric cancer patients with poor disease outcome.