Abstract
Abstract Background: SPARC (Secreted Protein Acidic and Rich in Cysteine) is an albumin-binding glycoprotein overexpressed in breast cancer and is associated with poor prognosis and shorter overall survival. We have previously shown that SPARC expression appeared to correlate with response to nanoparticle albumin-bound (nab) paclitaxel (Abraxane) in head-and-neck and pancreatic-cancer patients. To further define the role of SPARC, recombinant-human SPARC (rhSPARC) was characterized to identify its albumin-binding and angiogenic domain.Materials and methods: The albumin-binding site on SPARC was defined by testing the binding of Alexa 488-labeled BSA to immobilized rhSPARC in a solid-phase-binding assay and in a competitive-binding assay in presence of increasing concentration of various SPARC-derived peptides. The angiogenic activity of rhSPARC was evaluated using a HUVEC tube-formation assay.Results: The SPARC albumin-binding assay revealed a pattern of saturable and specific binding with an estimated Kd of 700 µM very near the known plasma concentration of albumin (600 µM). Competitive binding with Cathepsin K-digested SPARC and SPARC-derived peptides defined the albumin-binding domain to be amino acids 209-223 in the C-terminal region. In the HUVEC tube-formation assay, rhSPARC was pro-angiogenic at 10 µg/ml and anti-angiogenic at 100 µg/ml. The angiogenic domain of SPARC was located to the C-terminal of SPARC.Discussion: The albumin-binding domain of SPARC was located to residues aa209-223, supporting its role as a target for nab-technology-based drug delivery. We confirmed that SPARC can promote angiogenesis at physiological concentrations, contributing to the role of SPARC in a more aggressive tumor phenotype. The angiogenic domain of SPARC is located within a 54-aa sequence of its C-terminus. SPARC could be a potential therapeutic target and a biomarker for predicting response to nab-paclitaxel. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2144.
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