Neuropilin and its ligands in normal lung and cancer.

Neuropilins (NRPs) are receptors for class 3 Semaphorins and function as co-receptors for Vascular endothelial growth factor isoforms, VEGF(165) and VEGF(145) and related molecules. NRPs are expressed in a variety of neural and non-neural tissues and are required for normal development. Interestingly, class 3 Semaphorins and VEGF compete for common NRP binding. As a consequence, Semaphorins and VEGF appear to be mutually antagonistic. In the lung, NRP levels increase during development and NRPs and Semaphorins are involved in lung branching, probably by altering cell morphology or by regulating cell motility and migration. During lung tumorigenesis, both NRP and VEGF expression increase on dysplastic lung epithelial cells; SEMA3F expression is reduced and SEMA3F protein is delocalized from the membrane to the cytoplasm. In lung cancers, SEMA3F staining correlates inversely with tumor stage with high SEMAW associated with less aggressive tumors. Conversely, more aggressive tumors are associated with increased VEGF staining and a corresponding loss in membranous SEMA3F.