Although serum prostate specific antigen (PSA) is a well-established diagnostic tool for prostate cancer (PCa) detection, the definitive diagnosis of PCa is based on the information contained in prostate needle biopsy (PNBX) specimens. To define the proteomic features of PNBX specimens to identify candidate biomarkers for PCa, PNBX specimens from patients with PCa or benign prostatic hyperplasia (BPH) were subjected to comparative proteomic analysis. 2-DE revealed that 52 protein spots exhibited statistically significantly changes among PCa and BPH groups. Interesting spots were identified by MALDI-TOF-MS/MS. The 2 most notable groups of proteins identified included latent androgen receptor coregulators and FKBP4] and enzymes involved in mitochondrial fatty acid b-oxidation (DCI and ECHS1). An imbalance in the expression of peroxiredoxin subtypes was noted in PCa specimens. Furthermore, different post-translationally modified isoforms of HSP27 and HSP70.1 were identified. Importantly, changes in FLNA(7-15), FKBP4, and PRDX4 expression were confirmed by immunoblot analyses. Our results suggest that a proteomics-based approach is useful for developing a more complete picture of the protein profile of PNBX specimen. The proteins identified by this approach may be useful molecular targets for PCa diagnostics and therapeutics. ' 2007 Wiley-Liss, Inc.

Both the transforming growth factor b (TGF-b) and integrin signalling pathways have well-established roles in angiogenesis. However, how these pathways integrate to regulate angiogenesis is unknown. Here, we show that the extracellular matrix component, fibronectin, and its cellular receptor, a5b1 integrin, specifically increase TGF-b1-and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-b superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and a5b1 integrin increase Smad1/5/8 signalling by promoting endoglin/ ALK1 cell surface complex formation. In a reciprocal manner, TGF-b1 activates a5b1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglindependent manner. a5b1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating a5b1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/ a5b1 integrin and TGF-b pathway crosstalk alter the responses of endothelial cells to TGF-b1, switching TGF-b1 from a promoter to a suppressor of migration, inhibiting TGF-b1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-b superfamily signalling and endothelial function through crosstalk with integrin signalling pathways.

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