Mary Kay Francis
As individuals age, they are more likely to develop certain age-related pathologies such as metastatic tumors and vascular dysplasias. In fact, age has been shown to be the greatest risk for cancer development. Both we and others have recently shown that a gene, EPC-1/PEDF, which is expressed at high levels in young cells and is dramatically reduced in senescent cells, exhibits potent antiangiogenic activity toward vascular endothelial cells. The EPC-1 mRNA is expressed by fibroblasts and other cells of mesenchymal origin and is detected at elevated levels in the dermis of the skin. Since EPC-1/PEDF blocks the migration of endothelial cells both in vitro and in vivo, EPC-1/PEDF has the potential of inhibiting tumor metastasis in vivo by blocking the angiogenic response toward the tumor. In this scenario, the loss of EPC-1/PEDF with age adds a level of vulnerability for the development of metastatic tumors. We hypothesize that the dermis of elderly individuals contains an increased number of fibroblasts that have lost the ability to produce EPC-1/PEDF and that this loss of EPC-1/PEDF expression leads to an increased risk for tumor angiogenesis. We have examined the effect of EPC-1/PEDF on vascular endothelial growth factor (VEGF)-mediated signaling pathways, since VEGF is a critical element in the angiogenic response. Our results show that EPC-1/PEDF interferes with the autophosphorylation of the VEGF-R2 and downstream signaling events. It is not yet clear how EPC-1/PEDF interferes with the receptor phosphorylation. Understanding how EPC-1/PEDF interacts with the extracellular environment to control cellular migration and how this may be affected by the age-related decline in EPC-1/PEDF expression has profound implications for our comprehension of metastasis, macular degeneration, wound healing, and a host of chronic skin diseases that afflict elderly persons.