Collagens, laminins Fibronectin, ECM1, SPARC, osteopontin Collagen spl…

Collagens, laminins Fibronectin, ECM1, SPARC, osteopontin Collagen splice variants, nidogen, decorin, perlecan DBF4, GRK6, PAK2, FAK/ PTK2 Cystatin-M hsp90 CapG (actin-regulating protein) Caveolin-1 IGFBP5 CXCL1, IL-18 HGF HGF, MIP-1d, MIP-3a, NAP-2 14-3-3 zeta Cell redox proteins FAS pathway and caspase networkSome studies have focused on the ECM, others on tumor-stroma interactions and on immune cells infiltrating the tumor microenvironment. These studies have utilized various experimental systems applied to different tumor types. Some of the key proteins that have been found to be involved are highlighted, illustrating the numerous protein families that play a role in the tumor microenvironment. Abbreviations: CXCL1, interferon-inducible protein-1; DBF4, activator of S-phase kinase 4; GRK6, G-protein coupled receptor kinase 6; FAK, focal adhesion kinase; hsp90, heat shock protein 90; IGFBP5, insulin growth factor binding protein 5; IL-18, interleukin-18; IL1B, interleukin1B; MIP-1d, macrophage inflammatory protein-1d; MIP-3a, macrophage inflammatory protein-3a; MMP7, matrix metalloproteinase 7; NAP-2, neutrophil-activating peptide-2; PAK2, SPARC, secreted protein, acidic, cysteine rich; TME, tumor microenvironment.Proteases and their interactions with their inhibitors play a role in remodeling ECM and contribute to ECM composition. In a screen for proteins related to breast cancer metastasis to bone tissue, an inhibitor of several cathepsin proteases, cystatin-M (CST6), was observed to be downregulated [35]. Ectopic expression of CST6 suppressed metastasis in animal studies, whereas CST6 knockdown increased tumor aggressiveness [35]. Work by Blanco et al. [31] highlighted the interplay of ECM modulators consisting of the protease inhibitors CST1, CST2, and CST4 and the plasminogen-activating proteases PLAT and PLAU. The imbalance between matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) has been widely investigated [36]. Several studies have used proteomics to identify targets of membrane type 1 metalloprotease (MT1MMP), which has been proposed to play an important role in cell invasion [37,38]. Affinity purification of MT1-MMP identified 163 proteins associated with MT1-MMP through LC-MS/MS analysis [39]. Nine membrane proteins were confirmed to be cleaved by MT1-MMP by co-expression, including the Lutheran blood group glycoprotein (Lu). Tam et al. [40] identified new targets of MT1-MMP through an LC-MS/MS screen of isotope-labeled proteins from a breast cancercell line, confirming the substrates with MALDI. Interleukin-8 (IL-8) was shown PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/16989806 to be processed by MT1MMP to a more active form, whereas fibronectin expression was increased after Dasatinib MT1-MMP transfection. A novel proteomic approach, using fluorophore-assisted light inactivation (FALI) with antibody libraries for the identification of proteins related to invasiveness, revealed an extracellular form of hsp90 that acts as a chaperone for MMP2 and assists in its invasion-associated activation [41]. A comparison of high- and low-invasive ovarian cell lines confirmed that only cell lines expressing MT1-MMP were invasive through collagen-binding [41]. A targeted approach using the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse model found a general increase in the expression of ECMmodifying proteases, such as MMPs and cysteine proteases, during tumor progression [42]. Raf/MEK/ERK signaling disrupts tissue polarity in breast epitheli.