AGGF1 is a novel angiogenic factor that is, like vascular endothelial growth factor (VEGF), highly potent in proangiogenesis. AGGF1 protein (714 amino acids) is expressed in blood vessels and tumor cells. Unlike VEGF which binds to VEGFR2 to transduce its signals, preliminary data from our lab suggests that AGGF1 promotes angiogenesis by binding to its unique receptor, integrin alpha5beta1. Over-expression of AGGF1 promotes angiogenesis and AGGF1 knock down by RNA interference suppressed angiogenesis. Consistently, AGGF1+/- knockout mice had severe defects in the vasculature of embryos and yolk sacs.
Antiangiogenic therapy is a novel treatment for cancer. Clinical trials with angiogenesis inhibitors targeting the VEGF signaling pathway have shown promising outcomes. Currently the FDA has approved several antiangiogenic agents that target the VEGF pathway. However, to date, clinical efficacy of such therapy is still limited. More than 50% of patients do not respond to antiangiogenic treatments. Furthermore, the duration of response is modest and highly variable among different patients. These issues warrant further development of other alternative/complementary therapies to maximize the efficacy in cancer management.
AGGF1 can mediate endothelial adhesion, migration and capillary vessel formation. Although it has been established that AGGF1 is a potent angiogenic factor, its functional domain(s) involved in angiogenic processes remain unmapped. Our data shows that AGGF1-alpha5beta binding domain is at the C-terminal of AGGF1. The 10 amino acid binding domain of AGGF1 is also the angiogenic domain, involved in endothelial cell migration and tube formation. We demonstrate that peptides derived from the functional domain of AGGF1 inhibit AGGF1 binding to endothelial cells and also inhibit AGGF1-mediated endothelial tube formation. In vivo tumor angiogenesis assays show that AGGF1 peptide suppresses melanoma growth in mice. In summary, we have identified a novel peptide that can effectively block AGGF1 function and inhibit tumor growth.