VEGF-A and VEGFR-3 correlate with nodal status in operable non-small cell lung cancer: Inverse correlation between expression in tumor and stromal cells

BackgroundLymph node metastasis is an essential determinant for stage and clinical management of non-small cell lung cancer (NSCLC). The vascular endothelial growth factors (VEGFs) and receptors (VEGFRs) are fundamental molecules in angiogenesis and lymphangiogenesis. We aimed to explore the correlations between nodal metastasis and the expression of VEGFs and VEGFRs in tumor cells and in tumor-related stroma.Patients and methodsTumor tissue samples from 335 resected patients with stage I–IIIA NSCLC were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of VEGF-A, VEGF-C, and VEGF-D and VEGFR-1, VEGFR-2 and VEGFR-3.ResultsThere were 232 N0 and 103 N+ patients (76 N1, 27 N2). In multivariate analyses, low stromal VEGF-A expression (P = 0.018) is associated with N+ status. In tumor cells, strong correlations exist between high VEGF-A expression (P = 0.032) and N+ status, and high VEGFR-3 expression (P < 0.001) and N2-status.ConclusionThe converse impact by stromal VEGF-A versus tumor cell VEGF-A expression on nodal metastasis may allude the importance of the tumor–stroma interaction when trying to understand lymphatic metastasis in NSCLC.