Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L 19 VEEED 24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH 2 -kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34-and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDFbased tumor therapies. (Cancer Res 2005; 65(12): 5144-52)

Relaxin may have a useful application in decreasing interstitial fibrosis and thereby slowing the progression of renal disease.

MTA1 pro-angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa.

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Thrombospondin-1 is the first and most studied naturally occurring protein inhibitor of angiogenesis. Its characteristic multi-domain structure determines thrombospondin-1 divergent functions, which include but are not limited to the regulation of angiogenesis. Below we overview the structural determinants and receptors expressed on the endothelial and other cell types, that are at the root of thrombospondin-1 striking ability to block neovascularization. We specifically emphasize thrombospondin-1 direct apoptotic action on the remodeling vascular endothelium and summarize current knowledge of its pro-apoptotic signaling and transcriptional networks. Further, we provide comprehensive survey of the thrombospondin-based anti-angiogenic strategies with special focus on the combination treatments. We convincingly illustrate how precise knowledge of the pro-apoptotic events and intermediates elicited by thrombospondin in the vascular endothelial cells facilitates the design of the most effective treatment combinations, where the efficacy of thrombospondin-derived compounds is maximized by the partner drug(s) (“complementation” strategies) and provide examples of such fine-tuning of the thrombospondin-based anti-angiogenic treatments.