Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation

SPECIFIC AIMSWe investigated the relationship between vascular endothelial growth factor (VEGF)/VEGF receptor system and the secreted semaphorin-3A (Sema-3A) pathways in human mesothelial cells with the intent to identify molecular mechanisms differentially activated in malignant cells.PRINCIPAL FINDINGS1. VEGF induces cell growth in malignant but not in normal mesothelial cellsThe Met-5A mesothelial cell line, three different primary normal mesothelial cells (NM1, NM2, NM3), and three mesothelioma (MM) cell lines derived from untreated MM patients (MM1, MM2, MM3) constitutively express VEGF-R1, -R2, Np-1, and Np-2 at analogous levels by Western blot analysis. However, VEGF dose- and time-dependently reduced [3H]-thymidine uptake and cell growth in NM cells but increased DNA synthesis and cell growth in MM cells. Similar time-dependent VEGF-R2 phosphorylation by VEGF was observed in NM and MM cells. Thus, we found an opposite regulation of DNA synthesis rate by VEGF in NM cells and MM cells that could not...